Clemastine Fumarate as Remyelinating Treatment in Internuclear Ophthalmoparesis and Multiple Sclerosis

NCT ID: NCT05338450

Last Updated: 2024-11-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-08-30
• Study Completion Date: 2027-12-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Clemastine Fumarate

Group Type: EXPERIMENTAL

Clemastine Fumarate

Intervention Type: DRUG

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

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo equivalent to experimental arm

Interventions

Clemastine Fumarate

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

Intervention Type: DRUG

Placebo

Placebo equivalent to experimental arm

Intervention Type: DRUG

Other Intervention Names

clemastine; Tavegyl

Eligibility Criteria

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

• 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.

• 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.

• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: lead

Responsible Party

Sam Hof

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Axel Petzold, Dr.

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC, location VUmc

Locations

Amsterdam UMC, location VUmc

Amsterdam, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Sam Hof, MSc

Role: CONTACT

s.n.hof@amsterdamumc.nl

+3120444071

Facility Contacts

Sam Hof, MSc

Role: primary

s.n.hof@amsterdamumc.nl

+31204440717

References

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.

Reference Type: DERIVED

PMID: 38296293 (View on PubMed)

Other Identifiers

2021-003677-66

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL78363.029.21

Identifier Type: -

Identifier Source: org_study_id