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

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.

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).

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Placebo; Other: Imaging; Biological: Lumbar puncture; Biological: Blood sampling; Biological: Urine samples; Drug: Vitamin D

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 Type: Interventional
• Enrollment (Actual): 316
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens Cedex 1, France, 80054
    • CHU d'Amiens - Hôpital Nord
  • Bron, France, 69677
    • CHU de Lyon - Hôpital Pierre Wertheimer
  • Caen Cedex 9, France, 14033
    • CHU de Caen - Hopital Cote de Nacre
  • Clermont Ferrand, France, 63003
    • CHU de Clermont Ferrand - Hôpital Gabriel-Montpied
  • Corbeil-Essonnes, France, 91100
    • Ch Sud Francilien
  • Cornebarrieu, France, 31700
    • Clinique des Cèdres - Capio
  • Dijon, France, 21079
    • CHU de DIJON
  • Grenoble, France, 38043
    • CHU de Grenoble - Hôpital A Michallon
  • Lille, France, 59037
    • CHRU de Lille - Hôpital Roger Salengro
  • Limoges, France, 87042
    • Chu de Limoges - Hopital Dupuytren
  • Lomme Cedex, France, 59462
    • Groupe Hospitalier de l'Institut Catholique de Lille
  • Montpellier, France, 34295
    • CHU de Montpellier - Hôpital Gui de Chauliac
  • Nancy, France, 54035
    • CHU de Nancy - Hôpital Central
  • Nantes, France, 44093
    • CHU de Nantes - Hotel-Dieu
  • Nice, France, 06002
    • CHU de Nice - Hopital Pasteur
  • Nîmes Cedex 9, France, 30029
    • CHU de Nimes - Hopital Universitaire Caremeau
  • Paris, France, 75013
    • MAILLART Elisabeth - La Pitié Salpétrière
  • Paris, France, 75019
    • Fondation Ophtalmologique Adolphe Rothschild
  • Paris Cedex 12, France, 75571
    • APHP - Hôpital Saint-Antoine
  • Pau, France, 64000
    • CH de Pau
  • Perpignan, France, 66046
    • CH de Perpignan - Hôpital Saint Jean
  • Quimper, France, 29107
    • CH de Cornouaille - Site Quimper - Hôpital Laennec
  • Reims, France, 51092
    • CHU de Reims - Hôpital Maison Blanche
  • Rennes, France, 35033
    • CHU de Rennes - Hôpital Pontchaillou
  • Rouen, France, 76031
    • CHU de Rouen - Hôpital Charles Nicolle
  • Saint-Germain-en-Laye, France, 78100
    • CH de Poissy - Saint-Germain-en-Laye
  • Saumur Cedex, France, 49403
    • CH de SAUMUR
  • Strasbourg Cedex, France, 67091
    • CHRU de Strasbourg - Hôpital Civil
  • Toulouse Cedex 9, France, 31059
    • CHRU de Toulouse - Hôpital Purpan
  • Tours, France, 37044
    • CHRU de Tours - Hôpital Bretonneau
  • Versailles, France, 78000
    • CH de Versailles - Hôpital Mignot
  • Vichy, France, 03207
    • CH de Vichy - Jacques Larin
• Martinique
  • Fort-de-France, Martinique, 97200
    • CHU de Martinique - Hôpital Pierre Zobda-Quitman

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 52 years (Adult)
• Accepts Healthy Volunteers: No

Description

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 ....).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 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	Drug: Placebo; 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.; Other: Imaging; All patients are scheduled for MRI scans at baseline, 3 months, 12 months, 24 months, as well as upon conversion to full MS.; Other Names: Cerebro-medullar MRI; Biological: Lumbar puncture; A baseline collection of cerebral spinal fluid may be required for certain patients (doctor's decision.); Biological: Blood sampling; 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.; Biological: Urine samples; Urine samples are required of all patients at baseline, 3 months, 6 months, 12 months, 18 months, 24 months, and upon conversion to MS.
Experimental: Vit 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	Other: Imaging; All patients are scheduled for MRI scans at baseline, 3 months, 12 months, 24 months, as well as upon conversion to full MS.; Other Names: Cerebro-medullar MRI; Biological: Lumbar puncture; A baseline collection of cerebral spinal fluid may be required for certain patients (doctor's decision.); Biological: Blood sampling; 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.; Biological: Urine samples; Urine samples are required of all patients at baseline, 3 months, 6 months, 12 months, 18 months, 24 months, and upon conversion to MS.; Drug: Vitamin D; 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.; Other Names: Cholecalciferol

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Time Frame
DNA sample (blood sample) for biobank	baseline
Hemogram	baseline
Hemogram	3 months
Hemogram	6 months
Hemogram	12 months
Hemogram	18 months
Hemogram	24 months
Hemogram	upon conversion to MS (maximum 24 months)
alanine amino transferase serum levels	baseline
alanine amino transferase serum levels	3 months
alanine amino transferase serum levels	6 months
alanine amino transferase serum levels	12 months
alanine amino transferase serum levels	18 months
alanine amino transferase serum levels	24 months
alanine amino transferase serum levels	upon conversion to MS (maximum 24 months)
aspartate aminotransferase serum levels	baseline
aspartate aminotransferase serum levels	3 months
aspartate aminotransferase serum levels	6 months
aspartate aminotransferase serum levels	12 months
aspartate aminotransferase serum levels	18 months
aspartate aminotransferase serum levels	24 months
aspartate aminotransferase serum levels	upon conversion to MS (maximum 24 months)
alkaline phosphatase serum levels	baseline
alkaline phosphatase serum levels	3 months
alkaline phosphatase serum levels	6 months
alkaline phosphatase serum levels	12 months
alkaline phosphatase serum levels	18 months
alkaline phosphatase serum levels	24 months
alkaline phosphatase serum levels	upon conversion to MS (maximum 24 months)
serum calcium levels	baseline
serum calcium levels	3 months
serum calcium levels	6 months
serum calcium levels	12 months
serum calcium levels	18 months
serum calcium levels	24 months
serum calcium levels	upon conversion to MS (maximum 24 months)
serum creatinine levels	baseline
serum creatinine levels	3 months
serum creatinine levels	6 months
serum creatinine levels	12 months
serum creatinine levels	18 months
serum creatinine levels	24 months
serum creatinine levels	upon conversion to MS (maximum 24 months)
serum albumin levels	baseline
serum albumin levels	3 months
serum albumin levels	6 months
serum albumin levels	12 months
serum albumin levels	18 months
serum albumin levels	24 months
serum albumin levels	upon conversion to MS (maximum 24 months)
serum urea levels	baseline
serum urea levels	3 months
serum urea levels	6 months
serum urea levels	12 months
serum urea levels	18 months
serum urea levels	24 months
serum urea levels	upon conversion to MS (maximum 24 months)
serum bilirubin levels	baseline
serum bilirubin levels	3 months
serum bilirubin levels	6 months
serum bilirubin levels	12 months
serum bilirubin levels	18 months
serum bilirubin levels	24 months
serum bilirubin levels	upon conversion to MS (maximum 24 months)
serum electrolyte panel	baseline
serum electrolyte panel	3 months
serum electrolyte panel	6 months
serum electrolyte panel	12 months
serum electrolyte panel	18 months
serum electrolyte panel	24 months
serum electrolyte panel	upon conversion to MS (maximum 24 months)

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Investigators: Study Director: Eric Thouvennot, MD, PhD, Centre Hospitalier Universitaire de Nīmes; Principal Investigator: Eric Thouvenot, MD, PhD, Centre Hospitalier Universitaire de Nīmes

Study record dates

Study Major Dates

• Study Start: July 16, 2013
• Primary Completion (Actual): January 4, 2023
• Study Completion (Actual): January 4, 2023

Study Registration Dates

• First Submitted: March 20, 2013
• First Submitted That Met QC Criteria: March 20, 2013
• First Posted (Estimated): March 22, 2013

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: vitamin D; cholecalciferol; immune disease; clinically isolated syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: PHRC-N/2012/ET-01; 2012-005821-59 (EudraCT Number)