Internuclear Ophthalmoplegia, Multiple Sclerosis
Conditions
Keywords
clemastine, fampridine, remyelination, eye-tracking, infrared oculography
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.
Interventions
4 mg of Clemastine Fumarate twice daily (8mg/day) orally for 6 months (180 days)
DRUGPlacebo
Placebo equivalent to experimental arm
Sponsors
Amsterdam UMC, location VUmc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Versional Dysconjugacy Index (VDI) - Area Under the Curve (VDI-AUC) (6 months) | 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. |
| Versional Dysconjugacy Index (VDI) - Area Under the Curve (VDI-AUC) (36 months) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Other Versional Dysconjugacy Index (VDI) measures - Peak Velocity (VDI-pV + VDI-pV/Am) | 6 and 36 months | Changes in other VDI measures (peak velocity (PV) and peak velocity divided by amplitude (PV/Am)). |
| Versional Dysconjugacy Index (VDI) - Response to Fampridine | Baseline | Changes in VDI in response to single dose of Fampridine. |
| Other infrared oculography parameters - Saccadic Latency | 6 months and 36 months | Changes in saccadic latency measured by infrared oculography. |
| Other infrared oculography parameters - Proportion of errors in an anti-saccadic task | 6 months and 36 months | Changes in proportion of errors in an anti-saccadic task measured by infrared oculography. |
| Other infrared oculography parameters - Proportion of correct double-step saccades | 6 months and 36 months | Changes in the proportion of correct double-step saccades measured by infrared oculography. |
| Other infrared oculography parameters - Error of the final eye position in double-step saccades | 6 months and 36 months | Changes in the error of the final eye position in double-step saccades measured by infrared oculography. |
| Symbol Digit Modalities Test (SDMT) | 6 months and 36 months | — |
| Expanded Disability Status Scale (EDSS) | 6 months and 36 months | Changes in the Expanded Disability Status Scale (EDSS), which ranges from 0 (normal neurological exam, no disability) to 10.0 (death due to MS). |
| High and Low Contrast Visual Acuity (HCVA and LCVA) | 6 months and 36 months | — |
| Subjective visual functioning (NEI-VFQ-25) | 6 months and 36 months | Changes in subjective visual functioning measured by the National Eye Institute Visual Functioning Questionnaire - 25 (NEI-VFQ-25) questionnaire. |
| Visual complaints (NOV-AU) | 6 months and 36 months | Changes in visual complaints measured by the Neuro-Ophthalmology Questionnaire Amsterdam UMC (NOV-AU) questionnaire. |
| Quality of life (EQ5D-5L) | 6 months and 36 months | Changes in quality of life measured by EuroQol 5-Dimension 5-Level (EQ5D-5L) questionnaire. |
| Fatigue - CIS20R | 6 months and 36 months | Prevalence and changes in fatigue measured by the Checklist Individual Strength (CIS20R) questionnaire. |
| Fatigue - NFI-MS | 6 months and 36 months | Prevalence and changes in fatigue measured by the Neurological Fatigue Index MS (NFI-MS) questionnaire. |
Countries
Netherlands
Contacts
PRINCIPAL_INVESTIGATORAxel Petzold, Dr.
Amsterdam UMC, location VUmc
Outcome results
None listed