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

NCT ID: NCT01817166

Last Updated: 2024-01-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 316 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-07-16
• Study Completion Date: 2023-01-04

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.

Conditions

Multiple Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Imaging

Intervention Type: OTHER

All patients are scheduled for MRI scans at baseline, 3 months, 12 months, 24 months, as well as upon conversion to full MS.

Lumbar puncture

Intervention Type: BIOLOGICAL

A baseline collection of cerebral spinal fluid may be required for certain patients (doctor's decision.)

Blood sampling

Intervention Type: BIOLOGICAL

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.

Urine samples

Intervention Type: BIOLOGICAL

Urine samples are required of all patients at baseline, 3 months, 6 months, 12 months, 18 months, 24 months, and upon conversion to MS.

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

Group Type: EXPERIMENTAL

Vitamin D

Intervention Type: DRUG

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.

Imaging

Intervention Type: OTHER

All patients are scheduled for MRI scans at baseline, 3 months, 12 months, 24 months, as well as upon conversion to full MS.

Lumbar puncture

Intervention Type: BIOLOGICAL

A baseline collection of cerebral spinal fluid may be required for certain patients (doctor's decision.)

Blood sampling

Intervention Type: BIOLOGICAL

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.

Urine samples

Intervention Type: BIOLOGICAL

Urine samples are required of all patients at baseline, 3 months, 6 months, 12 months, 18 months, 24 months, and upon conversion to MS.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Imaging

All patients are scheduled for MRI scans at baseline, 3 months, 12 months, 24 months, as well as upon conversion to full MS.

Intervention Type: OTHER

Lumbar puncture

A baseline collection of cerebral spinal fluid may be required for certain patients (doctor's decision.)

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: BIOLOGICAL

Other Intervention Names

Cholecalciferol; Cerebro-medullar MRI

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 ....).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 56 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre Hospitalier Universitaire de Nīmes

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eric Thouvennot, MD, PhD

Role: STUDY_DIRECTOR

Centre Hospitalier Universitaire de Nîmes

Eric Thouvenot, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier Universitaire de Nîmes

Locations

CHU d'Amiens - Hôpital Nord

Amiens, , France

CHU de Lyon - Hôpital Pierre Wertheimer

Bron, , France

CHU de Caen - Hôpital Côte de Nacre

Caen, , France

CHU de Clermont Ferrand - Hôpital Gabriel-Montpied

Clermont-Ferrand, , France

CH Sud Francilien

Corbeil-Essonnes, , 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, , France

CHU de Montpellier - Hôpital Gui de Chauliac

Montpellier, , France

CHU de Nancy - Hôpital Central

Nancy, , France

CHU de Nantes - Hôtel-Dieu

Nantes, , France

CHU de Nice - Hôpital Pasteur

Nice, , France

CHU de Nîmes - Hôpital Universitaire Carémeau

Nîmes, , France

MAILLART Elisabeth - La Pitié Salpétrière

Paris, , France

Fondation Ophtalmologique Adolphe Rothschild

Paris, , France

APHP - Hôpital Saint-Antoine

Paris, , France

CH de Pau

Pau, , 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 Poissy - Saint-Germain-en-Laye

Saint-Germain-en-Laye, , France

CH de Saumur

Saumur, , France

CHRU de Strasbourg - Hôpital Civil

Strasbourg, , France

CHRU de Toulouse - Hôpital Purpan

Toulouse, , France

CHRU de Tours - Hôpital Bretonneau

Tours, , France

CH de Versailles - Hôpital Mignot

Versailles, , France

CH de Vichy - Jacques Larin

Vichy, , France

CHU de Martinique - Hôpital Pierre Zobda-Quitman

Fort-de-France, , Martinique

Countries

France; Martinique

References

Thouvenot E, Laplaud D, Lebrun-Frenay C, Derache N, Le Page E, Maillart E, Froment-Tilikete C, Castelnovo G, Casez O, Coustans M, Guennoc AM, Heinzlef O, Magy L, Nifle C, Ayrignac X, Fromont A, Gaillard N, Caucheteux N, Patry I, De Seze J, Deschamps R, Clavelou P, Biotti D, Edan G, Camu W, Agherbi H, Renard D, Demattei C, Fabbro-Peray P, Mura T, Rival M; D-Lay MS Investigators. High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial. JAMA. 2025 Apr 22;333(16):1413-1422. doi: 10.1001/jama.2025.1604.

Reference Type: DERIVED

PMID: 40063041 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2012-005821-59

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PHRC-N/2012/ET-01

Identifier Type: -

Identifier Source: org_study_id