Clinical trial NCT01817166: Efficacy of Cholecalciferol (Vitamin D3) for Delaying the Diagnosis of MS After a Clinically Isolated Syndrome
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: cholecalciferol
vitamin D
immune disease
clinically isolated syndrome
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Sponsor class: OTHER
First posted: 2013-03-22
Enrollment: 316
Sex: ALL
Minimum age (years): 18
Maximum age (years): 56
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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 ....).

Primary outcomes:
measure: Conversion to MS yes/no
timeFrame: 24 months
Secondary outcomes:
measure: Number of relapse episodes (number per year)
timeFrame: 24 months
measure: number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI
timeFrame: 3 months
measure: number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI
timeFrame: 12 months
measure: number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI
timeFrame: 24 months
measure: Number of new T1 lesions taking on Gadolinium highlighting
timeFrame: 3 months
measure: Number of new T1 lesions taking on Gadolinium highlighting
timeFrame: 12 months
measure: Number of new T1 lesions taking on Gadolinium highlighting
timeFrame: 24 months
measure: Number of hyposignal T1 lesions (black holes)
timeFrame: 3 months
measure: Number of hyposignal T1 lesions (black holes)
timeFrame: 12 months
measure: Number of hyposignal T1 lesions (black holes)
timeFrame: 24 months
measure: Lesional burden in mm^3 for each cerebral MRI
timeFrame: 3 months
measure: Lesional burden in mm^3 for each cerebral MRI
timeFrame: 12 months
measure: Lesional burden in mm^3 for each cerebral MRI
timeFrame: 24 months
measure: Total number of Gadolinium highlighted lesions on T1 images
timeFrame: 3 months
measure: Total number of Gadolinium highlighted lesions on T1 images
timeFrame: 12 months
measure: Total number of Gadolinium highlighted lesions on T1 images
timeFrame: 24 months
measure: Normalized cerebral volume (SIENAX) obtained from a T13D sequence
timeFrame: 3 months
measure: Normalized cerebral volume (SIENAX) obtained from a T13D sequence
timeFrame: 12 months
measure: Normalized cerebral volume (SIENAX) obtained from a T13D sequence
timeFrame: 24 months
measure: Change in global cerebral volume (mm^3)
timeFrame: baseline versus 24 months
measure: EDSS score, including all subscores
timeFrame: baseline
measure: EDSS score, including all subscores
timeFrame: 3 months
measure: EDSS score, including all subscores
timeFrame: 12 months
measure: EDSS score, including all subscores
timeFrame: 24 months
measure: EDSS score, including all subscores
timeFrame: after second MS episode (1st relapse)(maximum 24 months)
measure: score for the PASAT 3 seconds section of the MSFC score
timeFrame: baseline
measure: score for the PASAT 3 seconds section of the MSFC score
timeFrame: 3 months
measure: score for the PASAT 3 seconds section of the MSFC score
timeFrame: 12 months
measure: score for the PASAT 3 seconds section of the MSFC score
timeFrame: 24 months
measure: score for the PASAT 3 seconds section of the MSFC score
timeFrame: after second MS episode (1st relapse)(maximum 24 months)
measure: EQ5D questionnaire
timeFrame: baseline
measure: EQ5D questionnaire
timeFrame: 3 months
measure: EQ5D questionnaire
timeFrame: 12 months
measure: EQ5D questionnaire
timeFrame: 24 months
measure: SF36 questionnaire
timeFrame: baseline
measure: SF36 questionnaire
timeFrame: 3 months
measure: SF36 questionnaire
timeFrame: 12 months
measure: SF36 questionnaire
timeFrame: 24 months
measure: FSMC fatigue scale
timeFrame: baseline
measure: FSMC fatigue scale
timeFrame: 3 months
measure: FSMC fatigue scale
timeFrame: 12 months
measure: FSMC fatigue scale
timeFrame: 24 months
measure: TLS-QOL10 questionnaire
timeFrame: baseline
measure: TLS-QOL10 questionnaire
timeFrame: 3 months
measure: TLS-QOL10 questionnaire
timeFrame: 12 months
measure: TLS-QOL10 questionnaire
timeFrame: 24 months
measure: TLS-Coping10 questionnaire
timeFrame: baseline
measure: TLS-Coping10 questionnaire
timeFrame: 3 months
measure: TLS-Coping10 questionnaire
timeFrame: 12 months
measure: TLS-Coping10 questionnaire
timeFrame: 24 months
measure: HADS questionnaire
timeFrame: baseline
measure: HADS questionnaire
timeFrame: 3 months
measure: HADS questionnaire
timeFrame: 12 months
measure: HADS questionnaire
timeFrame: 24 months
measure: Presence/absence of adverse events
timeFrame: baseline
measure: Presence/absence of adverse events
timeFrame: 3 months
measure: Presence/absence of adverse events
timeFrame: 6 months
measure: Presence/absence of adverse events
timeFrame: 12 months
measure: Presence/absence of adverse events
timeFrame: 18 months
measure: Presence/absence of adverse events
timeFrame: 24 months
measure: 25(OH)D2+D3 serum level (nmol/l)
timeFrame: baseline
measure: 25(OH)D2+D3 serum level (nmol/l)
timeFrame: 3 months
measure: 25(OH)D2+D3 serum level (nmol/l)
timeFrame: 6 months
measure: 25(OH)D2+D3 serum level (nmol/l)
timeFrame: 12 months
measure: 25(OH)D2+D3 serum level (nmol/l)
timeFrame: 18 months
measure: 25(OH)D2+D3 serum level (nmol/l)
timeFrame: 24 months
measure: 25(OH)D2+D3 serum level (nmol/l)
timeFrame: upon conversion to MS (maximum 24 months)
measure: Calciuria/creatinuria
timeFrame: baseline
measure: Calciuria/creatinuria
timeFrame: 3 months
measure: Calciuria/creatinuria
timeFrame: 6 months
measure: Calciuria/creatinuria
timeFrame: 12 months
measure: Calciuria/creatinuria
timeFrame: 18 months
measure: Calciuria/creatinuria
timeFrame: 24 months
measure: Calciuria/creatinuria
timeFrame: upon conversion to MS (maximum 24 months)
measure: Delay until conversion to MS
timeFrame: 24 months
Other outcomes:
measure: DNA sample (blood sample) for biobank
timeFrame: baseline
measure: Hemogram
timeFrame: baseline
measure: Hemogram
timeFrame: 3 months
measure: Hemogram
timeFrame: 6 months
measure: Hemogram
timeFrame: 12 months
measure: Hemogram
timeFrame: 18 months
measure: Hemogram
timeFrame: 24 months
measure: Hemogram
timeFrame: upon conversion to MS (maximum 24 months)
measure: alanine amino transferase serum levels
timeFrame: baseline
measure: alanine amino transferase serum levels
timeFrame: 3 months
measure: alanine amino transferase serum levels
timeFrame: 6 months
measure: alanine amino transferase serum levels
timeFrame: 12 months
measure: alanine amino transferase serum levels
timeFrame: 18 months
measure: alanine amino transferase serum levels
timeFrame: 24 months
measure: alanine amino transferase serum levels
timeFrame: upon conversion to MS (maximum 24 months)
measure: aspartate aminotransferase serum levels
timeFrame: baseline
measure: aspartate aminotransferase serum levels
timeFrame: 3 months
measure: aspartate aminotransferase serum levels
timeFrame: 6 months
measure: aspartate aminotransferase serum levels
timeFrame: 12 months
measure: aspartate aminotransferase serum levels
timeFrame: 18 months
measure: aspartate aminotransferase serum levels
timeFrame: 24 months
measure: aspartate aminotransferase serum levels
timeFrame: upon conversion to MS (maximum 24 months)
measure: alkaline phosphatase serum levels
timeFrame: baseline
measure: alkaline phosphatase serum levels
timeFrame: 3 months
measure: alkaline phosphatase serum levels
timeFrame: 6 months
measure: alkaline phosphatase serum levels
timeFrame: 12 months
measure: alkaline phosphatase serum levels
timeFrame: 18 months
measure: alkaline phosphatase serum levels
timeFrame: 24 months
measure: alkaline phosphatase serum levels
timeFrame: upon conversion to MS (maximum 24 months)
measure: serum calcium levels
timeFrame: baseline
measure: serum calcium levels
timeFrame: 3 months
measure: serum calcium levels
timeFrame: 6 months
measure: serum calcium levels
timeFrame: 12 months
measure: serum calcium levels
timeFrame: 18 months
measure: serum calcium levels
timeFrame: 24 months
measure: serum calcium levels
timeFrame: upon conversion to MS (maximum 24 months)
measure: serum creatinine levels
timeFrame: baseline
measure: serum creatinine levels
timeFrame: 3 months
measure: serum creatinine levels
timeFrame: 6 months
measure: serum creatinine levels
timeFrame: 12 months
measure: serum creatinine levels
timeFrame: 18 months
measure: serum creatinine levels
timeFrame: 24 months
measure: serum creatinine levels
timeFrame: upon conversion to MS (maximum 24 months)
measure: serum albumin levels
timeFrame: baseline
measure: serum albumin levels
timeFrame: 3 months
measure: serum albumin levels
timeFrame: 6 months
measure: serum albumin levels
timeFrame: 12 months
measure: serum albumin levels
timeFrame: 18 months
measure: serum albumin levels
timeFrame: 24 months
measure: serum albumin levels
timeFrame: upon conversion to MS (maximum 24 months)
measure: serum urea levels
timeFrame: baseline
measure: serum urea levels
timeFrame: 3 months
measure: serum urea levels
timeFrame: 6 months
measure: serum urea levels
timeFrame: 12 months
measure: serum urea levels
timeFrame: 18 months
measure: serum urea levels
timeFrame: 24 months
measure: serum urea levels
timeFrame: upon conversion to MS (maximum 24 months)
measure: serum bilirubin levels
timeFrame: baseline
measure: serum bilirubin levels
timeFrame: 3 months
measure: serum bilirubin levels
timeFrame: 6 months
measure: serum bilirubin levels
timeFrame: 12 months
measure: serum bilirubin levels
timeFrame: 18 months
measure: serum bilirubin levels
timeFrame: 24 months
measure: serum bilirubin levels
timeFrame: upon conversion to MS (maximum 24 months)
measure: serum electrolyte panel
timeFrame: baseline
measure: serum electrolyte panel
timeFrame: 3 months
measure: serum electrolyte panel
timeFrame: 6 months
measure: serum electrolyte panel
timeFrame: 12 months
measure: serum electrolyte panel
timeFrame: 18 months
measure: serum electrolyte panel
timeFrame: 24 months
measure: serum electrolyte panel
timeFrame: upon conversion to MS (maximum 24 months)
Locations:
city: Amiens Cedex 1
country: France
facility: CHU d'Amiens - Hôpital Nord
city: Bron
country: France
facility: CHU de Lyon - Hôpital Pierre Wertheimer
city: Caen Cedex 9
country: France
facility: CHU de Caen - Hôpital Côte de Nacre
city: Clermont Ferrand
country: France
facility: CHU de Clermont Ferrand - Hôpital Gabriel-Montpied
city: Corbeil-Essonnes
country: France
facility: CH Sud Francilien
city: Cornebarrieu
country: France
facility: Clinique des Cèdres - Capio
city: Dijon
country: France
facility: CHU de Dijon
city: Grenoble
country: France
facility: CHU de Grenoble - Hôpital A Michallon
city: Lille
country: France
facility: CHRU de Lille - Hôpital Roger Salengro
city: Limoges
country: France
facility: CHU de Limoges - Hôpital Dupuytren
city: Lomme Cedex
country: France
facility: Groupe Hospitalier de l'Institut Catholique de Lille
city: Montpellier
country: France
facility: CHU de Montpellier - Hôpital Gui de Chauliac
city: Nancy
country: France
facility: CHU de Nancy - Hôpital Central
city: Nantes
country: France
facility: CHU de Nantes - Hôtel-Dieu
city: Nice
country: France
facility: CHU de Nice - Hôpital Pasteur
city: Nîmes Cedex 9
country: France
facility: CHU de Nîmes - Hôpital Universitaire Carémeau
city: Paris Cedex 12
country: France
facility: APHP - Hôpital Saint-Antoine
city: Paris
country: France
facility: MAILLART Elisabeth - La Pitié Salpétrière
city: Paris
country: France
facility: Fondation Ophtalmologique Adolphe Rothschild
city: Pau
country: France
facility: CH de Pau
city: Perpignan
country: France
facility: CH de Perpignan - Hôpital Saint Jean
city: Quimper
country: France
facility: CH de Cornouaille - Site Quimper - Hôpital Laennec
city: Reims
country: France
facility: CHU de Reims - Hôpital Maison Blanche
city: Rennes
country: France
facility: CHU de Rennes - Hôpital PontChaillou
city: Rouen
country: France
facility: CHU de Rouen - Hôpital Charles Nicolle
city: Saint-Germain-en-Laye
country: France
facility: CH de Poissy - Saint-Germain-en-Laye
city: Saumur Cedex
country: France
facility: CH de Saumur
city: Strasbourg Cedex
country: France
facility: CHRU de Strasbourg - Hôpital Civil
city: Toulouse Cedex 9
country: France
facility: CHRU de Toulouse - Hôpital Purpan
city: Tours
country: France
facility: CHRU de Tours - Hôpital Bretonneau
city: Versailles
country: France
facility: CH de Versailles - Hôpital Mignot
city: Vichy
country: France
facility: CH de Vichy - Jacques Larin
city: Fort-de-France
country: Martinique
facility: CHU de Martinique - Hôpital Pierre Zobda-Quitman
Study officials:
affiliation: Centre Hospitalier Universitaire de Nîmes
name: Eric Thouvennot, MD, PhD
role: STUDY_DIRECTOR
affiliation: Centre Hospitalier Universitaire de Nîmes
name: Eric Thouvenot, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: