Clemastine Fumarate as Remyelinating Treatment in Internuclear Ophthalmoparesis and Multiple Sclerosis

NCT05338450 | Terminated Phase 3

• 3 other identifiers: NL78363.029.212024-513099-17-002021-003677-66
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Multiple Sclerosis; Internuclear Ophthalmoplegia

Keywords

clemastine; fampridine; remyelination; eye-tracking; infrared oculography

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (14)

• Other Versional Dysconjugacy Index (VDI) measures - Peak Velocity (VDI-pV + VDI-pV/Am)

  6 and 36 months

• Versional Dysconjugacy Index (VDI) - Response to Fampridine

  Baseline

• Other infrared oculography parameters - Saccadic Latency

  6 months and 36 months

• Other infrared oculography parameters - Proportion of errors in an anti-saccadic task

  6 months and 36 months

• Other infrared oculography parameters - Proportion of correct double-step saccades

  6 months and 36 months

Study Arms (2)

Clemastine Fumarate

EXPERIMENTAL

Drug: Clemastine Fumarate

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Placebo DRUG

Placebo equivalent to experimental arm

Placebo

Clemastine Fumarate DRUG

4 mg of Clemastine Fumarate twice daily (8mg/day) orally for 6 months (180 days)

Also known as: clemastine, Tavegyl

Clemastine Fumarate

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).
• 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.
• Involvement in other study protocol simultaneously without prior approval.
• Insufficient proficiency in reading Dutch.

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead

Study Sites (1)

Amsterdam UMC, location VUmc

Amsterdam, 1081 HV, Netherlands

Location

Related Publications (1)

• Hof S, van Rijn LJ, Uitdehaag BMJ, Nij Bijvank JA, Petzold A. Measuring and predicting the effect of remyelinating therapy in multiple sclerosis: a randomised controlled trial protocol (RESTORE). BMJ Open. 2024 Jan 30;14(1):e076651. doi: 10.1136/bmjopen-2023-076651.

  PMID: 38296293 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis; Ocular Motility Disorders

Interventions

Clemastine

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Central Nervous System Diseases; Cranial Nerve Diseases; Eye Diseases

Intervention Hierarchy (Ancestors)

Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Axel Petzold, Dr.

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: April 6, 2022
• First Posted: April 21, 2022
• Study Start: August 30, 2022
• Primary Completion: August 15, 2025
• Study Completion: August 15, 2025
• Last Updated: May 6, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

NL (1)