Clemastine Fumarate as Remyelinating Treatment in Internuclear Ophthalmoparesis and Multiple Sclerosis

Inclusion criteria:

• A clinically definite diagnosis of multiple sclerosis.

• Diagnosis of internuclear ophthalmoparesis determined by the first infraredoculography at screening with either cut-off of 1.174 of the versional dysconjugacyindex area under the curve (VDI-AUC) of 15° saccades or 1.180 of the versionaldysconjugacy 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 anddated informed consent.

Exclusion criteria:

MS-related exclusion criteria:

• Changes in immunomodulatory therapy for multiple sclerosis in the 6 months beforeinclusion into the study.

• Clinical relapse of MS or high dosage corticosteroid use within 30 days beforeinclusion into the study.

IMP and medication related exclusion criteria:

• Contraindications to clemastine use, such as known porphyria or hypersensitivity toclemastine, other antihistamines with a similar chemical structure or any of theexcipients.

• Contraindications to fampridine use, such as hypersensitivity to fampridine or anyof the excipients, history of epilepsy, kidney disease (GFR <50 ml/min absolutecontraindication; GFR = 50-80 ml/min relative contraindication), use of OrganicCation Transporter 2 (OCT2) inhibitors or history of significant cardiac arrhythmiasor conduction block.

• Concomitant use of Fampridine or any other formulation of 4-aminopyridine (4AP) ordiamino4ap that cannot be temporarily suspended prior to each study visit.

• Changes in the use of medication currently being investigated in remyelinationtrials 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 limitedto hypnotics, anxiolytics, monoamine-oxidase inhibitors (MAOI'S), tricyclicantidepressants, 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 basalcell carcinoma of the skin or adequately treated cervical cancer), treated oruntreated, within the past 3 years, regardless of whether there is evidence of localrecurrence or metastases.

• Estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m2; AST, ALT, oralkaline phosphatase > 2 times the upper limit of normal.

• Any ophthalmological disease which may prevent accurate infrared oculographyassessment.

• 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 affectinterpretation of study results or patient safety.

• History of or presence of clinically significant medical illness or laboratoryabnormality that, in the opinion of the investigator would preclude participation inthe study.

General exclusion criteria:

• Pregnancy at the time of inclusion into the study or planning on breastfeedingwithin 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.