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

Multiple Sclerosis Clinical Trial

— D-Lay-MS  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01817166
• Other study ID #: PHRC-N/2012/ET-01
• Secondary ID: 2012-005821-59
• Status: Completed
• Phase: Phase 3
• Start date: July 16, 2013
• Est. completion date: January 4, 2023

Study information

• Verified date: January 2024
• Source: Centre Hospitalier Universitaire de Nimes
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 316
• Est. completion date: January 4, 2023
• Est. primary completion date: January 4, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 56 Years

Eligibility

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 ....).

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

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.
• 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.

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

Locations

Country	Name	City	State
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	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 Cedex
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 Cedex 9
France	Fondation Ophtalmologique Adolphe Rothschild	Paris
France	MAILLART Elisabeth - La Pitié Salpétrière	Paris
France	APHP - Hôpital Saint-Antoine	Paris Cedex 12
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 Cedex
France	CHRU de Strasbourg - Hôpital Civil	Strasbourg Cedex
France	CHRU de Toulouse - Hôpital Purpan	Toulouse Cedex 9
France	CHRU de Tours - Hôpital Bretonneau	Tours
France	CH de Versailles - Hôpital Mignot	Versailles
France	CH de Vichy - Jacques Larin	Vichy
Martinique	CHU de Martinique - Hôpital Pierre Zobda-Quitman	Fort-de-France

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Nimes

Countries where clinical trial is conducted

France,  Martinique, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	DNA sample (blood sample) for biobank		baseline
Other	Hemogram		baseline
Other	Hemogram		3 months
Other	Hemogram		6 months
Other	Hemogram		12 months
Other	Hemogram		18 months
Other	Hemogram		24 months
Other	Hemogram		upon conversion to MS (maximum 24 months)
Other	alanine amino transferase serum levels		baseline
Other	alanine amino transferase serum levels		3 months
Other	alanine amino transferase serum levels		6 months
Other	alanine amino transferase serum levels		12 months
Other	alanine amino transferase serum levels		18 months
Other	alanine amino transferase serum levels		24 months
Other	alanine amino transferase serum levels		upon conversion to MS (maximum 24 months)
Other	aspartate aminotransferase serum levels		baseline
Other	aspartate aminotransferase serum levels		3 months
Other	aspartate aminotransferase serum levels		6 months
Other	aspartate aminotransferase serum levels		12 months
Other	aspartate aminotransferase serum levels		18 months
Other	aspartate aminotransferase serum levels		24 months
Other	aspartate aminotransferase serum levels		upon conversion to MS (maximum 24 months)
Other	alkaline phosphatase serum levels		baseline
Other	alkaline phosphatase serum levels		3 months
Other	alkaline phosphatase serum levels		6 months
Other	alkaline phosphatase serum levels		12 months
Other	alkaline phosphatase serum levels		18 months
Other	alkaline phosphatase serum levels		24 months
Other	alkaline phosphatase serum levels		upon conversion to MS (maximum 24 months)
Other	serum calcium levels		baseline
Other	serum calcium levels		3 months
Other	serum calcium levels		6 months
Other	serum calcium levels		12 months
Other	serum calcium levels		18 months
Other	serum calcium levels		24 months
Other	serum calcium levels		upon conversion to MS (maximum 24 months)
Other	serum creatinine levels		baseline
Other	serum creatinine levels		3 months
Other	serum creatinine levels		6 months
Other	serum creatinine levels		12 months
Other	serum creatinine levels		18 months
Other	serum creatinine levels		24 months
Other	serum creatinine levels		upon conversion to MS (maximum 24 months)
Other	serum albumin levels		baseline
Other	serum albumin levels		3 months
Other	serum albumin levels		6 months
Other	serum albumin levels		12 months
Other	serum albumin levels		18 months
Other	serum albumin levels		24 months
Other	serum albumin levels		upon conversion to MS (maximum 24 months)
Other	serum urea levels		baseline
Other	serum urea levels		3 months
Other	serum urea levels		6 months
Other	serum urea levels		12 months
Other	serum urea levels		18 months
Other	serum urea levels		24 months
Other	serum urea levels		upon conversion to MS (maximum 24 months)
Other	serum bilirubin levels		baseline
Other	serum bilirubin levels		3 months
Other	serum bilirubin levels		6 months
Other	serum bilirubin levels		12 months
Other	serum bilirubin levels		18 months
Other	serum bilirubin levels		24 months
Other	serum bilirubin levels		upon conversion to MS (maximum 24 months)
Other	serum electrolyte panel		baseline
Other	serum electrolyte panel		3 months
Other	serum electrolyte panel		6 months
Other	serum electrolyte panel		12 months
Other	serum electrolyte panel		18 months
Other	serum electrolyte panel		24 months
Other	serum electrolyte panel		upon conversion to MS (maximum 24 months)
Primary	Conversion to MS yes/no	Conversion to MS according to criteria described by McDonald (Polman et al 2005)	24 months
Secondary	Number of relapse episodes (number per year)		24 months
Secondary	number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI		3 months
Secondary	number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI		12 months
Secondary	number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI		24 months
Secondary	Number of new T1 lesions taking on Gadolinium highlighting	qualitative variable: 0, 1, or >1	3 months
Secondary	Number of new T1 lesions taking on Gadolinium highlighting	qualitative variable: 0, 1, or >1	12 months
Secondary	Number of new T1 lesions taking on Gadolinium highlighting	qualitative variable: 0, 1, or >1	24 months
Secondary	Number of hyposignal T1 lesions (black holes)		3 months
Secondary	Number of hyposignal T1 lesions (black holes)		12 months
Secondary	Number of hyposignal T1 lesions (black holes)		24 months
Secondary	Lesional burden in mm^3 for each cerebral MRI		3 months
Secondary	Lesional burden in mm^3 for each cerebral MRI		12 months
Secondary	Lesional burden in mm^3 for each cerebral MRI		24 months
Secondary	Total number of Gadolinium highlighted lesions on T1 images	Exact number (semiautomatic measure)	3 months
Secondary	Total number of Gadolinium highlighted lesions on T1 images	Exact number (semiautomatic measure)	12 months
Secondary	Total number of Gadolinium highlighted lesions on T1 images	Exact number (semiautomatic measure)	24 months
Secondary	Normalized cerebral volume (SIENAX) obtained from a T13D sequence	mm^3	3 months
Secondary	Normalized cerebral volume (SIENAX) obtained from a T13D sequence	mm^3	12 months
Secondary	Normalized cerebral volume (SIENAX) obtained from a T13D sequence	mm^3	24 months
Secondary	Change in global cerebral volume (mm^3)		baseline versus 24 months
Secondary	EDSS score, including all subscores		baseline
Secondary	EDSS score, including all subscores		3 months
Secondary	EDSS score, including all subscores		12 months
Secondary	EDSS score, including all subscores		24 months
Secondary	EDSS score, including all subscores		after second MS episode (1st relapse)(maximum 24 months)
Secondary	score for the PASAT 3 seconds section of the MSFC score		baseline
Secondary	score for the PASAT 3 seconds section of the MSFC score		3 months
Secondary	score for the PASAT 3 seconds section of the MSFC score		12 months
Secondary	score for the PASAT 3 seconds section of the MSFC score		24 months
Secondary	score for the PASAT 3 seconds section of the MSFC score		after second MS episode (1st relapse)(maximum 24 months)
Secondary	EQ5D questionnaire		baseline
Secondary	EQ5D questionnaire		3 months
Secondary	EQ5D questionnaire		12 months
Secondary	EQ5D questionnaire		24 months
Secondary	SF36 questionnaire		baseline
Secondary	SF36 questionnaire		3 months
Secondary	SF36 questionnaire		12 months
Secondary	SF36 questionnaire		24 months
Secondary	FSMC fatigue scale		baseline
Secondary	FSMC fatigue scale		3 months
Secondary	FSMC fatigue scale		12 months
Secondary	FSMC fatigue scale		24 months
Secondary	TLS-QOL10 questionnaire		baseline
Secondary	TLS-QOL10 questionnaire		3 months
Secondary	TLS-QOL10 questionnaire		12 months
Secondary	TLS-QOL10 questionnaire		24 months
Secondary	TLS-Coping10 questionnaire		baseline
Secondary	TLS-Coping10 questionnaire		3 months
Secondary	TLS-Coping10 questionnaire		12 months
Secondary	TLS-Coping10 questionnaire		24 months
Secondary	HADS questionnaire		baseline
Secondary	HADS questionnaire		3 months
Secondary	HADS questionnaire		12 months
Secondary	HADS questionnaire		24 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	25(OH)D2+D3 serum level (nmol/l)		baseline
Secondary	25(OH)D2+D3 serum level (nmol/l)		3 months
Secondary	25(OH)D2+D3 serum level (nmol/l)		6 months
Secondary	25(OH)D2+D3 serum level (nmol/l)		12 months
Secondary	25(OH)D2+D3 serum level (nmol/l)		18 months
Secondary	25(OH)D2+D3 serum level (nmol/l)		24 months
Secondary	25(OH)D2+D3 serum level (nmol/l)		upon conversion to MS (maximum 24 months)
Secondary	Calciuria/creatinuria		baseline
Secondary	Calciuria/creatinuria		3 months
Secondary	Calciuria/creatinuria		6 months
Secondary	Calciuria/creatinuria		12 months
Secondary	Calciuria/creatinuria		18 months
Secondary	Calciuria/creatinuria		24 months
Secondary	Calciuria/creatinuria		upon conversion to MS (maximum 24 months)
Secondary	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