High-Dose Vitamin D Induction in Optic Neuritis

Study Overview
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Brief Summary
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This is a phase II randomized double-blind placebo/standard of care trial to determine if rapidly inducing vitamin D sufficiency in patients with acute optic neuritis results in less damage/greater recovery at 12 months as measured by optical coherence tomography, visual evoked potentials, visual acuity and radiological measures. Our hypothesis, based on earlier observational studies, is that acute optic neuritis in the context of vitamin D sufficiency results in better visual outcomes compared to those that are not sufficient acutely, regardless of such interventions as steroid therapy.

Detailed Description
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The present trial is based on the observation that vitamin D sufficiency appears to provide some degree of neuroprotection and/or repair in the context of an acute optic neuritis when followed over several months using optical coherence tomography measures. Based on these findings, this randomized double-blinded placebo/standard of care controlled trial has been designed to to see if rapidly inducing vitamin D sufficiency (defined in this trial as a serum 25(OH)D value => 80 nmol/L) results in relatively less reduction in neuroaxonal injury and/or improved recovery chronically (at month 12) versus those patients who do not achieve vitamin D sufficiency in the acute optic neuritis period. of Vitamin D. In this trial, 66 patients in total will be randomized to either high-dose vitamin D induction treatment group or the placebo/followed by standard of care vitamin D group and followed over 12 months.The primary measure of neuroaxonal integrity in this trial is optical coherence tomography outcomes including ganglion cell layer thickness, retinal nerve fiber layer thickness and macular volume. Other vision metrics and magnetic resonance imaging (MRI) measures will provide secondary outcome indicators of this as well.

Official Title
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A Phase II Trial of High-Dose Vitamin D Induction in Optic Neuritis (VitaDON 2)

Conditions
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Optic Neuritis

Intervention / Treatment
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* Drug: Vitamin D3
* Drug: Placebo/Standard of Care Vitamin D3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Canadian residents Patients must be between age 18 and 45 years Patients must have a diagnosis of either a CIS or RRMS (according to McDonald criteria) Patients must have an EDSS of 5.5 or less Patients must demonstrate features of a first typical optic neuritis within 21 days of recruitment (or must initiate treatment by day 30) Patients must have a baseline 25(OH)D < 80 nmol/L regardless of vitamin D3 supplementation Patients must have no contraindications to high-dose vitamin D supplementation Female patients must consent to use a reliable form of contraception (oral contraceptive pill, intrauterine device, barrier methods, abstinence) for the duration of the active treatment phase (first 90 days of where study drug provided) of the trial Patients must provide written informed consent. Exclusion Criteria: Patients who have had a previous optic neuritis Patients with evidence of a non-inflammatory cause of optic neuropathy Patients with evidence of neuromyelitis optica spectrum disorder or NMOSD (i.e. bilateral optic neuritis, MRI evidence of longitudinally enhancing lesions involving the optic nerves (involving three or more segments of the optic nerve), and/or involving the optic chiasm, and optic tracts Patients with a 25(OH)D > 80 nmol/L

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A double-blind randomized placebo/standard therapy phase II trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-Dose Vitamin D Treatment Group<br>Patients in this arm will receive: -5 days of high-dose oral vitamin D3 (50,000 IU daily x 5), followed by 85 days of moderate dose oral vitamin D3 (10,000 IU daily x 85 days) | Drug: Vitamin D3<br>* 50,000 IU/d of oral vitamin D3 x 5 days followed by 10,000 IU/d of oral vitamin D3 x 85 days<br>* Other names: Vitamin D - CHOLECALCIFEROL;|
| Placebo Comparator: Placebo/Standard Vitamin D3 Group<br>Patients in this arm will receive Placebo/Standard of Care Vitamin D3: -5 days of placebo, followed by 85 days of standard of care dose of oral vitamin D3 (4,000 IU daily x 85 days) | Drug: Placebo/Standard of Care Vitamin D3<br>* 50,000 IU/d of oral vitamin D3 x 5 days followed by 40,000 IU/d of oral vitamin D3 x 85 days<br>* Other names: Vitamin D - CHOLECALCIFEROL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inter-eye (IED) ganglion cell layer thickness (GCL) | The difference between the unaffected and affected eye GCL thickness between treatment and placebo group | month 12 | 
| Proportion of patients with GCL IED <= 8 microns | The proportion of patients with unaffected and affected eye GCL thickness of < = 8 microns between groups | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean GCL in affected eye over time | Rate of change in mean GCL thickness in affected eye over study between groups | baseline to 12 months | 
| Change in mean GCL in affected eye over time | Rate of change in mean GCL thickness in affected eye over study by 25(OH)D level | baseline to 12 months | 
| Change in mean GCL IED between eyes over time | Rate of change in mean GCL IED thickness in affected eye over study between groups | baseline to 12 months | 
| Change in mean GCL IED between eyes over time | Rate of change in mean GCL IED thickness in affected eye over study by 25(OH)D level | baseline to 12 months | 
| Change in mean retinal nerve fiber layer (RNFL) in affected eye over time | Rate of change in mean RNFL thickness in affected eye over study between groups | baseline to 12 months | 
| Change in mean RNFL in affected eye over time | Rate of change in mean RNFL thickness in affected eye over study by 25(OH)D level | baseline to 12 months | 
| Change in mean RNFL IED between eyes over time | Rate of change in mean RNFL and GCL thickness in affected eye over study between groups | baseline to 12 months | 
| Change in mean RNFL IED between eyes over time | Rate of change in mean RNFL and GCL thickness in affected eye over study by 25(OH)D level | baseline to 12 months | 
| Mean RNFL thickness | Mean RNFL thickness at baseline and months between groups | baseline | 
| Mean RNFL thickness | Mean RNFL thickness at month 1 between groups | 1 month | 
| Mean RNFL thickness | Mean RNFL thickness at month 6 between groups | 6 months | 
| Mean RNFL thickness | Mean RNFL thickness at month 12 between groups | 12 months | 
| Mean GCL thickness | Mean GCL thickness at baseline between groups | baseline to 12 months | 
| Mean GCL thickness | Mean GCL thickness at month 1 between groups | 1 month | 
| Mean GCL thickness | Mean GCL thickness at month 6 between groups | 6 months | 
| Mean GCL thickness | Mean GCL thickness at month 12 between groups | 12 months | 
| Inter-eye RNFL thickness | The difference between the unaffected and affected eye RNFL thickness at baseline between treatment and placebo groups | baseline to 12 months | 
| Inter-eye RNFL thickness | The difference between the unaffected and affected eye RNFL thickness at month 1 between treatment and placebo groups | 1 months | 
| Inter-eye RNFL thickness | The difference between the unaffected and affected eye RNFL thickness at month 6 between treatment and placebo groups | 6 months | 
| Inter-eye RNFL thickness | The difference between the unaffected and affected eye RNFL thickness at month 12 between treatment and placebo groups | 12 months | 
| Inter-eye GCL thickness | The difference between the unaffected and affected eye GCL thickness at baseline between treatment and placebo groups | baseline | 
| Inter-eye GCL thickness | The difference between the unaffected and affected eye GCL thickness at month 1 between treatment and placebo groups | 1 month | 
| Inter-eye GCL thickness | The difference between the unaffected and affected eye GCL thickness at month 6 between treatment and placebo groups | 6 months | 
| Inter-eye GCL thickness | The difference between the unaffected and affected eye RNFL thickness between treatment and placebo groups | 12 months | 
| Mean macular volume (MV) | Mean MV at baseline between groups | baseline | 
| Mean macular volume (MV) | Mean MV at month 1 between groups | 1 month | 
| Mean macular volume (MV) | Mean MV at month 6 between groups | 6 months | 
| Mean macular volume (MV) | Mean MV at month 12 between groups | 12 months | 
| Mean multifocal VEP (MfVEP) latency | Mean MfVEP at month 1 between groups | 1 month | 
| Mean change high and low contrast visual acuity (LogMAR) | Mean high and low contrast visual acuity (LogMAR) between groups at from baseline to month 12 | 12 months | 
| Correlation between baseline mean multifocal VEP latency and month-12 GCL, GCL inter-eye difference, RNFL and inter-eye RNFL difference between treatment and placebo groups | Correlation coefficient calculation between mean multifocal VEP latency at baseline and mean GCL, GCL inter-eye difference and RNFL and inter-eye RNFL difference at month 12 between treatment and placebo groups | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Optic Neuritis, Vitamin D