Efficacy of Cholecalciferol (Vitamin D3) for Delaying the Diagnosis of MS After a Clinically Isolated Syndrome

Study Overview
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Brief Summary
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The main objective of this study is to evaluate the efficacy and tolerance of 2 years of treatment with cholecalciferol (vitamin D3) in patients with a clinically isolated syndrome at high risk for MS (CIS).

Detailed Description
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The secondary objectives of this study are: A. evaluate clinical efficacy: delay to conversion; number of relapses/episodes per year B. evaluate efficacy in terms of resonance imaging parameters (cerebral/spinal MRI) C. evaluate efficacy in terms of slowing the progression of disability as measured by EDSS score and subscores D. measure and assess cognitive abilities (PASAT) E. evaluate changes in quality of life (EQ5D questionnaires, SF36, and TLS-TLS-QoL10 COPING10), fatigue questionnaire (FSMC) and anxiety / depression questionnaire (HADS) F. evaluate treatment tolerance G. to correlate changes in clinical and imaging parameters with the evolution of serum levels of 25(OH)D2 and 25(OH)D3 H. establish a biobank of DNA and RNA from all patients in the study and conduct analyses of gene polymorphisms involved in the metabolism of vitamin D and the HLA system based on the increased levels of vitamin D after supplementation I. establish a biobank of CSF, plasma, blood cells, serum and RNA samples for patients in selected centers for research on prognostic biomarkers of conversion J. establish a biobank consisting of plasma tubes collected for the determination of 25-hydroxy-vitamin D K. Estimate the rate of discordance between the conversion decision made by the study neurologist and the result of the MRI re-interpretation performed at the end of the study as well as the proportion of patients identified a posteriori as as erroneously included according to the centralized reading.

Official Title
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Multicentric, Randomized, Double-blind Versus Placebo Study Evaluating the Efficacy of Treatment With Cholecalciferol (Vitamin D3) for Delaying the Diagnosis of Multiple Sclerosis (MS) After a Clinically Isolated Syndrome (CIS). Comparison of Conversion Rates After 2 Years.

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Vitamin D
* Drug: Placebo
* Other: Imaging
* Biological: Lumbar puncture
* Biological: Blood sampling
* Biological: Urine samples


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient must have given his/her informed and signed consent The patient must be insured or beneficiary of a health insurance plan The patient is available for 24 months of follow-up The patient has had a classic CIS with the past 90 days Reference cerebro-medullary MRI scheduled within the 90 days after the beginning of symptoms With MRI (cerebro ± medullary) showing demyelination according to spatial spread criteria by Swanton (2006): At least 1 lesion in at least 2 of the 4 following territories: (1) Peri-ventricular; (2) Juxta-cortical; (3) Sub-tentorial; (4) Medullary No other suspected pathology Vitamin D level in blood less than 100 nmol / l at the pre-inclusion visit Women of childbearing potential must use very effective contraception for the duration of the study. A very effective contraceptive method is defined as a method resulting in a low failure rate (that is to say less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, IUDs, sexual abstinence, or partner with a vasectomy. Randomisation stratification criteria: The patient can also also meet the temporal dissemination criteria defined according to McDonald criteria 2010 (Polman et al., 2011), because this condition is currently not sufficient for prescribing a background treatment: Simultaneous presence of at least one asymptomatic lesion taking on contrast and at least one asymptomatic lesion not taking on contrast after injection of gadolinium Exclusion Criteria: The patient is participating in another study (this criteria does not apply to the POLAR study (RCB 2011-A01269-32); patients included in this study may simultaneously participate in the POLAR study) The patient is in an exclusion period determined by a previous study The patient is under judicial protection, under tutorship or curatorship The patient refuses to sign the consent It is impossible to correctly inform the patient The patient is pregnant, parturient, or breastfeeding Major medical or psychiatric illness that, according to the investigator, would result in the patient running an unnecessary risk or that could affect compliance with the study protocol Vitamin D insufficiency linked to currently active digestive or more general diseases (celiac disease, inflammatory bowel disease, intestinal bypass, short bowel syndrome, cirrhosis, nephrotic syndrome, hyperthyroidism, rickets, hypoparathyroidism, cancer, granulomatous diseases and lymphomas) Moderate or severe renal insufficiency (creatinine clearance less than 60 ml / min) Epilepsy not adequately controlled by treatment Any illness requiring chronic treatment with corticosteroids Patient with osteoporosis or history of osteopenia Pathology requiring calcium intakes greater than 1 gram per day Current or past history of hypercalcemia Medications that affect the metabolism of vitamin D other than corticosteroids; e.g. anticonvulsants [phenobarbital, primidone, phenytoin] rifampicin, isoniazid, ketoconazole, 5-FU and leucovorin, thiazide diuretics. Situations accompanied by increased vulnerability to hypercalcemia, e.g. arrhythmia or known heart disease, treatment with digitalis, and subjects with nephrolithiasis. Contraindications to vitamin D3 as mentioned in the documentation for UVEDOSE Known hypersensitivity to gadolinium and / or known inability to undergo an MRI (pacemaker, osteosynthesis material, intraocular metal splinter, etc ....).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 56 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Patients in this arm will receive a placebo treatment mimicking 100.000 UI of cholecalciferol every 14 days for a maximum of 24 months or until conversion to full multiple sclerosis has occurred. Intervention: Placebo Intervention: Imaging Intervention: Lumbar puncture Intervention: Blood sampling Intervention: Urine samples | Drug: Placebo<br>* Patients will receive a placebo treatment mimicking 100.000 UI of cholecalciferol every 14 days for a maximum of 24 months or until conversion to full multiple sclerosis has occurred.<br>Other: Imaging<br>* All patients are scheduled for MRI scans at baseline, 3 months, 12 months, 24 months, as well as upon conversion to full MS.<br>* Other names: Cerebro-medullar MRI;Biological: Lumbar puncture<br>* A baseline collection of cerebral spinal fluid may be required for certain patients (doctor's decision.)<br>Biological: Blood sampling<br>* Blood sampling is required of all patients at baseline, 3 months, 6 months, 12 months, 18 months and 24 months, as well as upon conversion to MS.<br>Biological: Urine samples<br>* Urine samples are required of all patients at baseline, 3 months, 6 months, 12 months, 18 months, 24 months, and upon conversion to MS.<br>|
| Experimental: Vit D<br>Patients in this arm will receive 100.000 UI of cholecalciferol every 14 days for a maximum of 24 months or until conversion to full multiple sclerosis has occurred. Intervention: Vitamin D Intervention: Imaging Intervention: Lumbar puncture Intervention: Blood sampling Intervention: Urine samples | Drug: Vitamin D<br>* Patients will receive 100.000 UI of cholecalciferol every 14 days for a maximum of 24 months or until conversion to full multiple sclerosis has occurred.<br>* Other names: Cholecalciferol;Other: Imaging<br>* All patients are scheduled for MRI scans at baseline, 3 months, 12 months, 24 months, as well as upon conversion to full MS.<br>* Other names: Cerebro-medullar MRI;Biological: Lumbar puncture<br>* A baseline collection of cerebral spinal fluid may be required for certain patients (doctor's decision.)<br>Biological: Blood sampling<br>* Blood sampling is required of all patients at baseline, 3 months, 6 months, 12 months, 18 months and 24 months, as well as upon conversion to MS.<br>Biological: Urine samples<br>* Urine samples are required of all patients at baseline, 3 months, 6 months, 12 months, 18 months, 24 months, and upon conversion to MS.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Conversion to MS yes/no | Conversion to MS according to criteria described by McDonald (Polman et al 2005) | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of relapse episodes (number per year) |  | 24 months | 
| number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI |  | 3 months | 
| number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI |  | 12 months | 
| number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI |  | 24 months | 
| Number of new T1 lesions taking on Gadolinium highlighting | qualitative variable: 0, 1, or >1 | 3 months | 
| Number of new T1 lesions taking on Gadolinium highlighting | qualitative variable: 0, 1, or >1 | 12 months | 
| Number of new T1 lesions taking on Gadolinium highlighting | qualitative variable: 0, 1, or >1 | 24 months | 
| Number of hyposignal T1 lesions (black holes) |  | 3 months | 
| Number of hyposignal T1 lesions (black holes) |  | 12 months | 
| Number of hyposignal T1 lesions (black holes) |  | 24 months | 
| Lesional burden in mm^3 for each cerebral MRI |  | 3 months | 
| Lesional burden in mm^3 for each cerebral MRI |  | 12 months | 
| Lesional burden in mm^3 for each cerebral MRI |  | 24 months | 
| Total number of Gadolinium highlighted lesions on T1 images | Exact number (semiautomatic measure) | 3 months | 
| Total number of Gadolinium highlighted lesions on T1 images | Exact number (semiautomatic measure) | 12 months | 
| Total number of Gadolinium highlighted lesions on T1 images | Exact number (semiautomatic measure) | 24 months | 
| Normalized cerebral volume (SIENAX) obtained from a T13D sequence | mm^3 | 3 months | 
| Normalized cerebral volume (SIENAX) obtained from a T13D sequence | mm^3 | 12 months | 
| Normalized cerebral volume (SIENAX) obtained from a T13D sequence | mm^3 | 24 months | 
| Change in global cerebral volume (mm^3) |  | baseline versus 24 months | 
| EDSS score, including all subscores |  | baseline | 
| EDSS score, including all subscores |  | 3 months | 
| EDSS score, including all subscores |  | 12 months | 
| EDSS score, including all subscores |  | 24 months | 
| EDSS score, including all subscores |  | after second MS episode (1st relapse)(maximum 24 months) | 
| score for the PASAT 3 seconds section of the MSFC score |  | baseline | 
| score for the PASAT 3 seconds section of the MSFC score |  | 3 months | 
| score for the PASAT 3 seconds section of the MSFC score |  | 12 months | 
| score for the PASAT 3 seconds section of the MSFC score |  | 24 months | 
| score for the PASAT 3 seconds section of the MSFC score |  | after second MS episode (1st relapse)(maximum 24 months) | 
| EQ5D questionnaire |  | baseline | 
| EQ5D questionnaire |  | 3 months | 
| EQ5D questionnaire |  | 12 months | 
| EQ5D questionnaire |  | 24 months | 
| SF36 questionnaire |  | baseline | 
| SF36 questionnaire |  | 3 months | 
| SF36 questionnaire |  | 12 months | 
| SF36 questionnaire |  | 24 months | 
| FSMC fatigue scale |  | baseline | 
| FSMC fatigue scale |  | 3 months | 
| FSMC fatigue scale |  | 12 months | 
| FSMC fatigue scale |  | 24 months | 
| TLS-QOL10 questionnaire |  | baseline | 
| TLS-QOL10 questionnaire |  | 3 months | 
| TLS-QOL10 questionnaire |  | 12 months | 
| TLS-QOL10 questionnaire |  | 24 months | 
| TLS-Coping10 questionnaire |  | baseline | 
| TLS-Coping10 questionnaire |  | 3 months | 
| TLS-Coping10 questionnaire |  | 12 months | 
| TLS-Coping10 questionnaire |  | 24 months | 
| HADS questionnaire |  | baseline | 
| HADS questionnaire |  | 3 months | 
| HADS questionnaire |  | 12 months | 
| HADS questionnaire |  | 24 months | 
| Presence/absence of adverse events | Presence/absence of adverse events the severity of which will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3. Grades I, II, III, IV, V. | baseline | 
| Presence/absence of adverse events | Presence/absence of adverse events the severity of which will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3. Grades I, II, III, IV, V. | 3 months | 
| Presence/absence of adverse events | Presence/absence of adverse events the severity of which will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3. Grades I, II, III, IV, V. | 6 months | 
| Presence/absence of adverse events | Presence/absence of adverse events the severity of which will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3. Grades I, II, III, IV, V. | 12 months | 
| Presence/absence of adverse events | Presence/absence of adverse events the severity of which will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3. Grades I, II, III, IV, V. | 18 months | 
| Presence/absence of adverse events | Presence/absence of adverse events the severity of which will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3. Grades I, II, III, IV, V. | 24 months | 
| 25(OH)D2+D3 serum level (nmol/l) |  | baseline | 
| 25(OH)D2+D3 serum level (nmol/l) |  | 3 months | 
| 25(OH)D2+D3 serum level (nmol/l) |  | 6 months | 
| 25(OH)D2+D3 serum level (nmol/l) |  | 12 months | 
| 25(OH)D2+D3 serum level (nmol/l) |  | 18 months | 
| 25(OH)D2+D3 serum level (nmol/l) |  | 24 months | 
| 25(OH)D2+D3 serum level (nmol/l) |  | upon conversion to MS (maximum 24 months) | 
| Calciuria/creatinuria |  | baseline | 
| Calciuria/creatinuria |  | 3 months | 
| Calciuria/creatinuria |  | 6 months | 
| Calciuria/creatinuria |  | 12 months | 
| Calciuria/creatinuria |  | 18 months | 
| Calciuria/creatinuria |  | 24 months | 
| Calciuria/creatinuria |  | upon conversion to MS (maximum 24 months) | 
| Delay until conversion to MS | The number of days that pass from the beginning of treatment to conversion to MS according to McDonald 2005 criteria (Polman et al 2005) | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cholecalciferol, vitamin D, immune disease, clinically isolated syndrome