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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 : January 9, 2023
Sponsor:
Collaborator:
Moorfields Eye Hospital NHS Foundation Trust
Information provided by (Responsible Party):
University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE August 10, 2015
First Posted Date  ICMJE August 13, 2015
Last Update Posted Date January 9, 2023
Actual Study Start Date  ICMJE February 28, 2017
Estimated Primary Completion Date August 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2017)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 10, 2015)
  • 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.
  • 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 28, 2021)
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2015)
  • Change in P100 latency on full-field visual evoked potential [ Time Frame: baseline, 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.
  • 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.
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Assessment of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis (ReCOVER)
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Optic Neuritis
Intervention  ICMJE
  • 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
  • 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.
Study Arms  ICMJE
  • Experimental: Clemastine
    Participants will receive clemastine until 3 months and then will be off treatment until 9 month time point.
    Intervention: Drug: Clemastine
  • Placebo Comparator: Placebo
    Participants will receive placebo until 3 months and then will be off treatment until 9 month time point.
    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 9, 2018)
90
Original Estimated Enrollment  ICMJE
 (submitted: August 10, 2015)
30
Estimated Study Completion Date  ICMJE August 2024
Estimated Primary Completion Date August 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients diagnosed or suspected to have an acute demyelinating optic neuritis in at least one eye within 3 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 the period of trial (women)
  • Understand and sign the informed consent

Exclusion Criteria:

  • Other major ophthalmologic diseases / concomitant ophthalmologic disorders (e.g. diabetes, macular degeneration, glaucoma, severe myopia, etc)
  • Disc hemorrhages in the qualifying eye
  • No light perception in qualifying eye
  • Simultaneous bilateral optic neuritis
  • Cotton wool spots in the qualifying eye
  • Macular star in the 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 protocols simultaneously without prior approval
  • Concomitant use of any other putative remyelinating therapy as determined by the 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 the 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.
  • Positive for NMO antibody discovered within the first 2 weeks after randomization.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shivany Y Condor Montes, MPH 415.353.2707 shivany.condormontes@ucsf.edu
Contact: Daniel Casillas, BA 805.663.7723‬ daniel.casillas@ucsf.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02521311
Other Study ID Numbers  ICMJE 15-17428
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party University of California, San Francisco
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of California, San Francisco
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Moorfields Eye Hospital NHS Foundation Trust
Investigators  ICMJE
Principal Investigator: Ari Green, MD, MCR University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date January 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP