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Assessment of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis (ReCOVER) (ReCOVER)

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ClinicalTrials.gov Identifier: NCT02521311
Recruitment Status : Recruiting
First Posted : August 13, 2015
Last Update Posted : November 14, 2018
Sponsor:
Collaborator:
Moorfields Eye Hospital NHS Foundation Trust
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
The main purpose of this study is to assess clemastine as a remyelinating agent in patients with acute optic neuritis.The study will also evaluate the tolerability of clemastine, originally approved as first-generation antihistamine, in patients with optic neuritis. Study procedures will include assessments for evidence of remyelination in the anterior visual pathway and in the brain using electrophysiologic techniques and magnetic resonance imaging. If they are on one, patients in this study can remain on their standard disease modifying treatment during the course of the study. However, patients cannot participate in any other investigational new drug research study concurrently.

Condition or disease Intervention/treatment Phase
Optic Neuritis Drug: Clemastine Drug: Placebo Phase 2

Detailed Description:

Optic neuritis is an inflammatory, demyelinating disease of the optic nerve. It is most often characterized by visual loss or blurred vision along with dyschromatopsiaaccompanied by pain (especially with eye movement) and no demonstrable evidence of an alternate diagnosis such as ischemia or retinal disease. It can also be associated with a swollen optic disc (Optic Neuritis Study Group 1991, Hutchinson, W.M. 1976) and optic nerve enhancement on MRI (Kupersmith 2002).

Functional high-throughput screening for compounds that promote remyelination presents a major unmet need in the therapeutic arsenal for multiple sclerosis and other demyelinating conditions such as optic neuritis. Screening for myelin repair is problematic, as functional remyelination requires the presence of intact neuronal axons. Standard methods are not suited for high-throughput formats. We performed a detailed screen of over 1500 FDA approved small molecule drugs to identify agents that could be promising for remyelination. Engineered with conical dimensions, our micropillar technology permitted resolution of the extent and length of membrane wrapping from a single 2-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for the fluorescence detection of concentric wrapping observed as "rings" of myelin membrane. The platform was formatted in 96-well plates, amenable to semi-automated random acquisition and automated detection and quantification. Upon initiating a screen of 1500 bioactive molecules, we identified Clemastine as a compound that potentially enhances oligodendrocyte differentiation and remyelination. We then validated this and other drugs in preclinical assays as well as in animal models of primary myelination and remyelination after inflammatory and chemical demyelination. Together, our findings illustrate the proof of concept for a novel high-throughput screening platform for potential regenerative therapeutics in MS (Chan JR et al. 2014).

This study is intended to assess for clinical evidence of remyelination using Clemastine Fumarate in patients with acute inflammatory injury causing demyelination of the anterior visual pathway as a consequence of acute demyelinating optic neuritis. 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. This study is complementary to an earlier study evaluating clemastine in chronic demyelinated optic neuropathy and serves as part of a proof of concept program intended to evaluate methods for conducting remyelination trials in MS.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Parallel-Group, Placebo Controlled Trial to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis
Study Start Date : August 2016
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Clemastine
Participants will receive clemastine until 3 months and then will be off treatment until 9 month time point.
Drug: Clemastine
12mg (4mg 3x/day) clemastine for 7 days followed by 8mg clemastine (4mg 2x/day) until 3 months. Patients will be off treatment from 3-9 months and will be reevaluated at 9 months.
Other Names:
  • Tavist
  • Clemastine fumarate
  • Walhist

Placebo Comparator: Placebo
Participants will receive placebo until 3 months and then will be off treatment until 9 month time point.
Drug: Placebo
Equivalent placebo. 12mg (4mg 3x/day) placebo for 7 days followed by 8mg placebo (4mg 2x/day) until 3 months. Patients will be off treatment from 3-9 months and will be reevaluated at 9 months.




Primary Outcome Measures :
  1. Change in P100 latency on full-field visual evoked potential [ Time Frame: baseline, 1 week, 1 month, 3 months, 9 months ]
    To evaluate the efficacy of clemastine relative to placebo for reducing P100 latencies on full field transient pattern reversal visual evoked potentials. Measure will be reported as difference in P100 latency from baseline to 9 months.

  2. Change in low contrast visual acuity [ Time Frame: baseline, 1 week, 1 month, 3 months, 9 months ]
    The second primary outcome is to measure the effectiveness of clemastine relative to placebo at improving patient performance on ETDRS low contrast visual acuity chart testing (2.5% black on white) during the recovery from an acute optic neuritis. Measure will be reported as difference in ETDRS score from baseline to 9 months.


Secondary Outcome Measures :
  1. Change in retinal nerve fiber layer thickness on optical coherence tomography [ Time Frame: baseline, 1 week, 1 month, 3 months, 9 months ]
    The primary outcome is to measure the effectiveness of clemastine relative to placebo at preventing the loss of retinal nerve fiber assessed via optical coherence tomography (OCT). Measure will be reported as difference in nerve fiber thickness between baseline and 9 months.

  2. Radiological outcomes assessed by magnetic resonance imaging [ Time Frame: baseline, 9 month ]
    To evaluate the efficacy of clemastine relative to placebo in increasing magnetization transfer ratios and myelin water fraction derived from magnetic resonance imaging of the brain during the period of exposure to active treatment. Measures will be reported as change between baseline and 9 months.

  3. Pupillary light response: pupillometry [ Time Frame: baseline, 1-week, 1-month, 3-month, 5-month ]
    To use pupillometry to evaluate the effectiveness of Clemastine in preventing a decreased light response in optic neuritis. Pupillometry has been shown to be an effective and sensitive way to evaluate changes in optic nerve function. Measure will be reported as the difference in light sensitivity as evaluated by pupillometry at baseline and 9 months.

  4. Expanded Disability Status Scale score [ Time Frame: baseline, 9 months ]
    To evaluate the efficacy of Clemastine relative to placebo in reducing the EDSS score at 9 months.The EDSS is an ordinal scale used for assessing neurological impairment of MS based on a neurological examination. It consists of scores in each of seven functional systems (FS) and an ambulation score that are then combined to determine the EDSS [ranging from 0 (normal) to 10 (death due to MS)]. The FSs are the Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel & Bladder, and Cerebral functions. The FSs and EDSS steps will be assessed in a standardized manner. EDSS is a widely used and accepted instrument to evaluate disability status at a given time and longitudinally, to assess disability progression in clinical studies in MS.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients diagnosed or suspected to have an acute demyelinating optic neuritis in at least one eye within 2 weeks from the onset of any visual symptom other than pain
  • Use of disease modifying therapies is not a contraindication
  • Use of appropriate contraception during period of trial (women)
  • Understand and signed informed consent

Exclusion Criteria:

  • Other major ophthalmologic disease / concomitant ophthalmologic disorders (e.g. diabetes, macular degeneration, glaucoma, severe myopia, etc)
  • Disc hemorrhages in qualifying eye
  • No light perception in qualifying eye
  • Simultaneous bilateral optic neuritis
  • Cotton wool spots in qualifying eye
  • Macular star in qualifying eye
  • 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 protocol simultaneously without prior approval
  • Concomitant use of any other putative remyelinating therapy as determined by investigator
  • Serum creatinine > 1.5 mg/dL; aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase > 2 times the upper limit of normal
  • 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 interpretation of study results or patient safety
  • History or presence of clinically significant medical illness or laboratory abnormality that, in the opinion of the investigator would preclude participation in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02521311


Contacts
Contact: Tracy Tran, BA 415-353-2707 tracy.tran@ucsf.edu

Locations
United States, California
University of California San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Tracy Tran, BA    415-353-2707    tracy.tran@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
Moorfields Eye Hospital NHS Foundation Trust
Investigators
Principal Investigator: Ari Green, MD, MCR University of California, San Francisco

Publications:
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02521311     History of Changes
Other Study ID Numbers: 15-17428
First Posted: August 13, 2015    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of California, San Francisco:
multiple sclerosis
eye pain
vision loss

Additional relevant MeSH terms:
Neuritis
Optic Neuritis
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Optic Nerve Diseases
Cranial Nerve Diseases
Eye Diseases
Clemastine
Antipruritics
Dermatologic Agents
Histamine H1 Antagonists
Histamine Antagonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Allergic Agents