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

Phase 3

Completed

• Conditions: Multiple Sclerosis
• Interventions: Drug: Placebo; Drug: Vitamin D; Other: Imaging; Biological: Lumbar puncture; Biological: Blood sampling; Biological: Urine samples

• Registration Number: NCT01817166
• Lead Sponsor: Centre Hospitalier Universitaire de Nīmes

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2013-03-20
• Study First Submitted QC: 2013-03-20
• Study First Posted: 2013-03-22
• Study Start: 2013-07-16
• Primary Completion: 2023-01-04
• Study Completion: 2023-01-04
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-11
• Last Update Posted: 2024-01-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 316

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

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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 ....).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Imaging	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
Placebo	Lumbar puncture	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
Placebo	Urine samples	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
Vit D	Lumbar puncture	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
Vit D	Blood sampling	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
Placebo	Blood sampling	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
Vit D	Imaging	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
Placebo	Placebo	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
Vit D	Vitamin D	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
Vit D	Urine samples	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

Primary Outcome Measures

Name	Time	Method
Conversion to MS yes/no	24 months	Conversion to MS according to criteria described by McDonald (Polman et al 2005)

Secondary Outcome Measures

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

Trial Locations

Locations (33)

CH de Pau; 🇫🇷 Pau, France

CHU d'Amiens - Hôpital Nord; 🇫🇷 Amiens Cedex 1, France

CHU de Lyon - Hôpital Pierre Wertheimer; 🇫🇷 Bron, France

CHU de Caen - Hôpital Côte de Nacre; 🇫🇷 Caen Cedex 9, France

CH Sud Francilien; 🇫🇷 Corbeil-Essonnes, France

CHU de Clermont Ferrand - Hôpital Gabriel-Montpied; 🇫🇷 Clermont Ferrand, France

Clinique des Cèdres - Capio; 🇫🇷 Cornebarrieu, France

CHU de Dijon; 🇫🇷 Dijon, France

CHU de Grenoble - Hôpital A Michallon; 🇫🇷 Grenoble, France

CHRU de Lille - Hôpital Roger Salengro; 🇫🇷 Lille, France

CHU de Limoges - Hôpital Dupuytren; 🇫🇷 Limoges, France

Groupe Hospitalier de l'Institut Catholique de Lille; 🇫🇷 Lomme Cedex, France

CHU de Nancy - Hôpital Central; 🇫🇷 Nancy, France

CHU de Nantes - Hôtel-Dieu; 🇫🇷 Nantes, France

CHU de Montpellier - Hôpital Gui de Chauliac; 🇫🇷 Montpellier, France

MAILLART Elisabeth - La Pitié Salpétrière; 🇫🇷 Paris, France

CHU de Nice - Hôpital Pasteur; 🇫🇷 Nice, France

CHU de Nîmes - Hôpital Universitaire Carémeau; 🇫🇷 Nîmes Cedex 9, France

APHP - Hôpital Saint-Antoine; 🇫🇷 Paris Cedex 12, France

Fondation Ophtalmologique Adolphe Rothschild; 🇫🇷 Paris, France

CH de Perpignan - Hôpital Saint Jean; 🇫🇷 Perpignan, France

CH de Cornouaille - Site Quimper - Hôpital Laennec; 🇫🇷 Quimper, France

CHU de Reims - Hôpital Maison Blanche; 🇫🇷 Reims, France

CHU de Rennes - Hôpital PontChaillou; 🇫🇷 Rennes, France

CHU de Rouen - Hôpital Charles Nicolle; 🇫🇷 Rouen, France

CH de Saumur; 🇫🇷 Saumur Cedex, France

CHRU de Toulouse - Hôpital Purpan; 🇫🇷 Toulouse Cedex 9, France

CH de Poissy - Saint-Germain-en-Laye; 🇫🇷 Saint-Germain-en-Laye, France

CHRU de Strasbourg - Hôpital Civil; 🇫🇷 Strasbourg Cedex, France

CHRU de Tours - Hôpital Bretonneau; 🇫🇷 Tours, France

CH de Vichy - Jacques Larin; 🇫🇷 Vichy, France

CH de Versailles - Hôpital Mignot; 🇫🇷 Versailles, France

CHU de Martinique - Hôpital Pierre Zobda-Quitman; 🇲🇶 Fort-de-France, Martinique