Clemastine Fumarate as Remyelinating Treatment in Internuclear Ophthalmoparesis and Multiple Sclerosis (RESTORE)

Rationale: Clemastine fumarate has been identified as potential remyelinating therapy for multiple sclerosis (MS). The (long-term) effects of clemastine need to be confirmed in clinical models for MS. Internuclear ophthalmoparesis (INO) may be used as a clinical model for investigating remyelinating therapies by measuring horizontal eye movements with infrared oculography. Furthermore, infrared oculography combined with a single dose of fampridine may be used to identify individuals with MS that are most likely to benefit from remyelinating therapy.

Objective: To assess the (long-term) efficacy of clemastine fumarate in improving dysconjugacy of eye movements in patients with internuclear ophthalmoparesis and multiple sclerosis. Secondly, to assess whether a response to a single dose of fampridine can predict the effects of clemastine treatment.

Study design: A single-centre double-blind randomized placebo-controlled trial consisting of a 6 months (180 days) treatment period followed by a 30 months follow-up period.

Study population: 80 MS patients, age 18-70 years, with INO.

Intervention: The intervention group will receive 4 mg of clemastine fumarate twice daily (8 mg/day) for 6 months (180 days), the control group will receive an equivalent amount of placebo. At baseline all participants will receive a single 10 mg dose of fampridine.

Main study parameters/endpoints: The primary outcome measure is the change in versional dysconjugacy index (VDI) of area under the curve (AUC) measured by infrared oculography. Secondary outcome measures include changes in other VDI measures (peak velocity per amplitude (PV/Am) and peak velocity (PV)), changes in VDI after single fampridine dose, other oculography parameters (e.g. saccadic latency, anti-saccades), (peripheral) retinal nerve fibre layer (pRNFL) and (macular) ganglion cell inner plexiform layer (mGCIPL) thickness measured by OCT, SDMT, EDSS, high and low contrast visual acuity, subjective visual functioning (NEI-VFQ-25 and NOV-AU questionnaire), quality of life (EQ5D-5L) and fatigue (CIS20R and NFI-MS questionnaire).

Nature and extent of the burden and risks: Participation in the study will consist of a total of 7 study visits. Study visits will include physical/neurological examination, infrared oculography, OCT, visual acuity tests, a cognition test (SDMT), 5 questionnaires and blood samples for safety laboratory tests. Considering both clemastine and fampridine are registered and well-established drugs and have been used in clinical practice, the estimated risk of unexpected adverse reactions is low.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis; Internuclear Ophthalmoplegia
• Intervention / Treatment: Drug: Clemastine Fumarate; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sam Hof, MSc; Phone Number: +3120444071; Email: s.n.hof@amsterdamumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Recruiting
    • Amsterdam UMC, location VUmc
    • Contact: Sam Hof, MSc; Phone Number: +31204440717; Email: s.n.hof@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• A clinically definite diagnosis of multiple sclerosis.
• Diagnosis of internuclear ophthalmoparesis determined by the first infrared oculography at screening with either cut-off of 1.174 of the versional dysconjugacy index area under the curve (VDI-AUC) of 15° saccades or 1.180 of the versional dysconjugacy index peak velocity/saccadic amplitude (VDI-PV/Am) of 15° saccades.
• Age 18-70 (inclusive)
• Use of disease modifying therapies is not a contraindication.
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent.

Exclusion criteria:

MS-related exclusion criteria:

• Changes in immunomodulatory therapy for multiple sclerosis in the 6 months before inclusion into the study.
• Clinical relapse of MS or high dosage corticosteroid use within 30 days before inclusion into the study.

IMP and medication related exclusion criteria:

• Contraindications to clemastine use, such as known porphyria or hypersensitivity to clemastine, other antihistamines with a similar chemical structure or any of the excipients.
• Contraindications to fampridine use, such as hypersensitivity to fampridine or any of the excipients, history of epilepsy, kidney disease (GFR <50 ml/min absolute contraindication; GFR = 50-80 ml/min relative contraindication), use of Organic Cation Transporter 2 (OCT2) inhibitors or history of significant cardiac arrhythmias or conduction block.
• Concomitant use of Fampridine or any other formulation of 4-aminopyridine (4AP) or diamino4ap that cannot be temporarily suspended prior to each study visit.
• Changes in the use of medication currently being investigated in remyelination trials within 6 months before screening, including but not limited to domperidone, liothyronine, quetiapine, testosterone and bazedoxifene.
• Non-incidental use of central nervous system depressants including but not limited to hypnotics, anxiolytics, monoamine-oxidase inhibitors (MAOI'S), tricyclic antidepressants, opioid analgesics and other antihistamines with sedating properties (e.g. promethazine).

Other medical history and concomitant disease exclusion criteria:

• History of significant cardiac conduction block.
• History of malignancy of any organ system (other than localized squamous or basal cell carcinoma of the skin or adequately treated cervical cancer), treated or untreated, within the past 3 years, regardless of whether there is evidence of local recurrence or metastases.
• Estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m2; AST, ALT, or alkaline phosphatase > 2 times the upper limit of normal.
• Any ophthalmological disease which may prevent accurate infrared oculography assessment.
• Suicidal ideation or behaviour in 6 months prior to baseline.
• History of drug or alcohol abuse within the past year.
• Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic, urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic, renal or other major diseases that in the PI's judgement may affect 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.

General exclusion criteria:

• Pregnancy at the time of inclusion into the study or planning on breastfeeding within the first 7 months after inclusion in the study.
• Involvement in other study protocol simultaneously without prior approval.
• Insufficient proficiency in reading Dutch.
• Unable or unwilling to suspend driving for a duration of 6 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo equivalent to experimental arm
Experimental: Clemastine Fumarate	Drug: Clemastine Fumarate; 4 mg of Clemastine Fumarate twice daily (8mg/day) orally for 6 months (180 days); Other Names: clemastine; Tavegyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Versional Dysconjugacy Index (VDI) - Area Under the Curve (VDI-AUC) (6 months)	Our main study parameter is the versional dysconjugacy index (VDI) measured by infrared oculography. The relative change in VDI from baseline will be compared between the treatment and control group at the end of treatment (6 months). The VDI of Area Under the Curve (AUC) will be our primary study parameter. This describes the area under the saccadic trajectory of the horizontal eye position.	6 months
Versional Dysconjugacy Index (VDI) - Area Under the Curve (VDI-AUC) (36 months)	The relative change in VDI from baseline will be compared between the treatment and control group at the end of follow-up (36 months).	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other Versional Dysconjugacy Index (VDI) measures - Peak Velocity (VDI-pV + VDI-pV/Am)	Changes in other VDI measures (peak velocity (PV) and peak velocity divided by amplitude (PV/Am)).	6 and 36 months
Versional Dysconjugacy Index (VDI) - Response to Fampridine	Changes in VDI in response to single dose of Fampridine.	Baseline
Other infrared oculography parameters - Saccadic Latency	Changes in saccadic latency measured by infrared oculography.	6 months and 36 months
Other infrared oculography parameters - Proportion of errors in an anti-saccadic task	Changes in proportion of errors in an anti-saccadic task measured by infrared oculography.	6 months and 36 months
Other infrared oculography parameters - Proportion of correct double-step saccades	Changes in the proportion of correct double-step saccades measured by infrared oculography.	6 months and 36 months
Other infrared oculography parameters - Error of the final eye position in double-step saccades	Changes in the error of the final eye position in double-step saccades measured by infrared oculography.	6 months and 36 months
Symbol Digit Modalities Test (SDMT)		6 months and 36 months
Expanded Disability Status Scale (EDSS)	Changes in the Expanded Disability Status Scale (EDSS), which ranges from 0 (normal neurological exam, no disability) to 10.0 (death due to MS).	6 months and 36 months
High and Low Contrast Visual Acuity (HCVA and LCVA)		6 months and 36 months
Subjective visual functioning (NEI-VFQ-25)	Changes in subjective visual functioning measured by the National Eye Institute Visual Functioning Questionnaire - 25 (NEI-VFQ-25) questionnaire.	6 months and 36 months
Visual complaints (NOV-AU)	Changes in visual complaints measured by the Neuro-Ophthalmology Questionnaire Amsterdam UMC (NOV-AU) questionnaire.	6 months and 36 months
Quality of life (EQ5D-5L)	Changes in quality of life measured by EuroQol 5-Dimension 5-Level (EQ5D-5L) questionnaire.	6 months and 36 months
Fatigue - CIS20R	Prevalence and changes in fatigue measured by the Checklist Individual Strength (CIS20R) questionnaire.	6 months and 36 months
Fatigue - NFI-MS	Prevalence and changes in fatigue measured by the Neurological Fatigue Index MS (NFI-MS) questionnaire.	6 months and 36 months

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: Axel Petzold, Dr., Amsterdam UMC, location VUmc

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2022
• Primary Completion (Anticipated): May 1, 2024
• Study Completion (Anticipated): November 1, 2026

Study Registration Dates

• First Submitted: April 6, 2022
• First Submitted That Met QC Criteria: April 13, 2022
• First Posted (Actual): April 21, 2022

Study Record Updates

• Last Update Posted (Actual): September 23, 2022
• Last Update Submitted That Met QC Criteria: September 21, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: remyelination; eye-tracking; clemastine; fampridine; infrared oculography
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Eye Diseases; Neurologic Manifestations; Cranial Nerve Diseases; Paralysis; Multiple Sclerosis; Sclerosis; Ophthalmoplegia; Ocular Motility Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Dermatologic Agents; Anti-Allergic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Clemastine
• Other Study ID Numbers: NL78363.029.21; 2021-003677-66 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No