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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01817166
Recruitment Status : Recruiting
First Posted : March 22, 2013
Last Update Posted : December 10, 2019
Sponsor:
Information provided by (Responsible Party):
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).

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Vitamin D Drug: Placebo Other: Imaging Biological: Lumbar puncture Biological: Blood sampling Biological: Urine samples Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 316 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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 Start Date : July 16, 2013
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023

Resource links provided by the National Library of Medicine


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 Name: 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

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 Name: Cholecalciferol

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 Name: 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.




Primary Outcome Measures :
  1. Conversion to MS yes/no [ Time Frame: 24 months ]
    Conversion to MS according to criteria described by McDonald (Polman et al 2005)


Secondary Outcome Measures :
  1. Number of relapse episodes (number per year) [ Time Frame: 24 months ]
  2. number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI [ Time Frame: 3 months ]
  3. number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI [ Time Frame: 12 months ]
  4. number of new brain lesions found in FLAIR MRI or medullary lesions found in T2 MRI [ Time Frame: 24 months ]
  5. Number of new T1 lesions taking on Gadolinium highlighting [ Time Frame: 3 months ]
    qualitative variable: 0, 1, or >1

  6. Number of new T1 lesions taking on Gadolinium highlighting [ Time Frame: 12 months ]
    qualitative variable: 0, 1, or >1

  7. Number of new T1 lesions taking on Gadolinium highlighting [ Time Frame: 24 months ]
    qualitative variable: 0, 1, or >1

  8. Number of hyposignal T1 lesions (black holes) [ Time Frame: 3 months ]
  9. Number of hyposignal T1 lesions (black holes) [ Time Frame: 12 months ]
  10. Number of hyposignal T1 lesions (black holes) [ Time Frame: 24 months ]
  11. Lesional burden in mm^3 for each cerebral MRI [ Time Frame: 3 months ]
  12. Lesional burden in mm^3 for each cerebral MRI [ Time Frame: 12 months ]
  13. Lesional burden in mm^3 for each cerebral MRI [ Time Frame: 24 months ]
  14. Total number of Gadolinium highlighted lesions on T1 images [ Time Frame: 3 months ]
    Exact number (semiautomatic measure)

  15. Total number of Gadolinium highlighted lesions on T1 images [ Time Frame: 12 months ]
    Exact number (semiautomatic measure)

  16. Total number of Gadolinium highlighted lesions on T1 images [ Time Frame: 24 months ]
    Exact number (semiautomatic measure)

  17. Normalized cerebral volume (SIENAX) obtained from a T13D sequence [ Time Frame: 3 months ]
    mm^3

  18. Normalized cerebral volume (SIENAX) obtained from a T13D sequence [ Time Frame: 12 months ]
    mm^3

  19. Normalized cerebral volume (SIENAX) obtained from a T13D sequence [ Time Frame: 24 months ]
    mm^3

  20. Change in global cerebral volume (mm^3) [ Time Frame: baseline versus 24 months ]
  21. EDSS score, including all subscores [ Time Frame: baseline ]
  22. EDSS score, including all subscores [ Time Frame: 3 months ]
  23. EDSS score, including all subscores [ Time Frame: 12 months ]
  24. EDSS score, including all subscores [ Time Frame: 24 months ]
  25. EDSS score, including all subscores [ Time Frame: after second MS episode (1st relapse)(maximum 24 months) ]
  26. score for the PASAT 3 seconds section of the MSFC score [ Time Frame: baseline ]
  27. score for the PASAT 3 seconds section of the MSFC score [ Time Frame: 3 months ]
  28. score for the PASAT 3 seconds section of the MSFC score [ Time Frame: 12 months ]
  29. score for the PASAT 3 seconds section of the MSFC score [ Time Frame: 24 months ]
  30. score for the PASAT 3 seconds section of the MSFC score [ Time Frame: after second MS episode (1st relapse)(maximum 24 months) ]
  31. EQ5D questionnaire [ Time Frame: baseline ]
  32. EQ5D questionnaire [ Time Frame: 3 months ]
  33. EQ5D questionnaire [ Time Frame: 12 months ]
  34. EQ5D questionnaire [ Time Frame: 24 months ]
  35. SF36 questionnaire [ Time Frame: baseline ]
  36. SF36 questionnaire [ Time Frame: 3 months ]
  37. SF36 questionnaire [ Time Frame: 12 months ]
  38. SF36 questionnaire [ Time Frame: 24 months ]
  39. FSMC fatigue scale [ Time Frame: baseline ]
  40. FSMC fatigue scale [ Time Frame: 3 months ]
  41. FSMC fatigue scale [ Time Frame: 12 months ]
  42. FSMC fatigue scale [ Time Frame: 24 months ]
  43. TLS-QOL10 questionnaire [ Time Frame: baseline ]
  44. TLS-QOL10 questionnaire [ Time Frame: 3 months ]
  45. TLS-QOL10 questionnaire [ Time Frame: 12 months ]
  46. TLS-QOL10 questionnaire [ Time Frame: 24 months ]
  47. TLS-Coping10 questionnaire [ Time Frame: baseline ]
  48. TLS-Coping10 questionnaire [ Time Frame: 3 months ]
  49. TLS-Coping10 questionnaire [ Time Frame: 12 months ]
  50. TLS-Coping10 questionnaire [ Time Frame: 24 months ]
  51. HADS questionnaire [ Time Frame: baseline ]
  52. HADS questionnaire [ Time Frame: 3 months ]
  53. HADS questionnaire [ Time Frame: 12 months ]
  54. HADS questionnaire [ Time Frame: 24 months ]
  55. Presence/absence of adverse events [ Time Frame: baseline ]
    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.

  56. Presence/absence of adverse events [ Time Frame: 3 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.

  57. Presence/absence of adverse events [ Time Frame: 6 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.

  58. Presence/absence of adverse events [ Time Frame: 12 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.

  59. Presence/absence of adverse events [ Time Frame: 18 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.

  60. Presence/absence of adverse events [ Time Frame: 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.

  61. 25(OH)D2+D3 serum level (nmol/l) [ Time Frame: baseline ]
  62. 25(OH)D2+D3 serum level (nmol/l) [ Time Frame: 3 months ]
  63. 25(OH)D2+D3 serum level (nmol/l) [ Time Frame: 6 months ]
  64. 25(OH)D2+D3 serum level (nmol/l) [ Time Frame: 12 months ]
  65. 25(OH)D2+D3 serum level (nmol/l) [ Time Frame: 18 months ]
  66. 25(OH)D2+D3 serum level (nmol/l) [ Time Frame: 24 months ]
  67. 25(OH)D2+D3 serum level (nmol/l) [ Time Frame: upon conversion to MS (maximum 24 months) ]
  68. Calciuria/creatinuria [ Time Frame: baseline ]
  69. Calciuria/creatinuria [ Time Frame: 3 months ]
  70. Calciuria/creatinuria [ Time Frame: 6 months ]
  71. Calciuria/creatinuria [ Time Frame: 12 months ]
  72. Calciuria/creatinuria [ Time Frame: 18 months ]
  73. Calciuria/creatinuria [ Time Frame: 24 months ]
  74. Calciuria/creatinuria [ Time Frame: upon conversion to MS (maximum 24 months) ]
  75. Delay until conversion to MS [ Time Frame: 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)


Other Outcome Measures:
  1. DNA sample (blood sample) for biobank [ Time Frame: baseline ]
  2. Hemogram [ Time Frame: baseline ]
  3. Hemogram [ Time Frame: 3 months ]
  4. Hemogram [ Time Frame: 6 months ]
  5. Hemogram [ Time Frame: 12 months ]
  6. Hemogram [ Time Frame: 18 months ]
  7. Hemogram [ Time Frame: 24 months ]
  8. Hemogram [ Time Frame: upon conversion to MS (maximum 24 months) ]
  9. alanine amino transferase serum levels [ Time Frame: baseline ]
  10. alanine amino transferase serum levels [ Time Frame: 3 months ]
  11. alanine amino transferase serum levels [ Time Frame: 6 months ]
  12. alanine amino transferase serum levels [ Time Frame: 12 months ]
  13. alanine amino transferase serum levels [ Time Frame: 18 months ]
  14. alanine amino transferase serum levels [ Time Frame: 24 months ]
  15. alanine amino transferase serum levels [ Time Frame: upon conversion to MS (maximum 24 months) ]
  16. aspartate aminotransferase serum levels [ Time Frame: baseline ]
  17. aspartate aminotransferase serum levels [ Time Frame: 3 months ]
  18. aspartate aminotransferase serum levels [ Time Frame: 6 months ]
  19. aspartate aminotransferase serum levels [ Time Frame: 12 months ]
  20. aspartate aminotransferase serum levels [ Time Frame: 18 months ]
  21. aspartate aminotransferase serum levels [ Time Frame: 24 months ]
  22. aspartate aminotransferase serum levels [ Time Frame: upon conversion to MS (maximum 24 months) ]
  23. alkaline phosphatase serum levels [ Time Frame: baseline ]
  24. alkaline phosphatase serum levels [ Time Frame: 3 months ]
  25. alkaline phosphatase serum levels [ Time Frame: 6 months ]
  26. alkaline phosphatase serum levels [ Time Frame: 12 months ]
  27. alkaline phosphatase serum levels [ Time Frame: 18 months ]
  28. alkaline phosphatase serum levels [ Time Frame: 24 months ]
  29. alkaline phosphatase serum levels [ Time Frame: upon conversion to MS (maximum 24 months) ]
  30. serum calcium levels [ Time Frame: baseline ]
  31. serum calcium levels [ Time Frame: 3 months ]
  32. serum calcium levels [ Time Frame: 6 months ]
  33. serum calcium levels [ Time Frame: 12 months ]
  34. serum calcium levels [ Time Frame: 18 months ]
  35. serum calcium levels [ Time Frame: 24 months ]
  36. serum calcium levels [ Time Frame: upon conversion to MS (maximum 24 months) ]
  37. serum creatinine levels [ Time Frame: baseline ]
  38. serum creatinine levels [ Time Frame: 3 months ]
  39. serum creatinine levels [ Time Frame: 6 months ]
  40. serum creatinine levels [ Time Frame: 12 months ]
  41. serum creatinine levels [ Time Frame: 18 months ]
  42. serum creatinine levels [ Time Frame: 24 months ]
  43. serum creatinine levels [ Time Frame: upon conversion to MS (maximum 24 months) ]
  44. serum albumin levels [ Time Frame: baseline ]
  45. serum albumin levels [ Time Frame: 3 months ]
  46. serum albumin levels [ Time Frame: 6 months ]
  47. serum albumin levels [ Time Frame: 12 months ]
  48. serum albumin levels [ Time Frame: 18 months ]
  49. serum albumin levels [ Time Frame: 24 months ]
  50. serum albumin levels [ Time Frame: upon conversion to MS (maximum 24 months) ]
  51. serum urea levels [ Time Frame: baseline ]
  52. serum urea levels [ Time Frame: 3 months ]
  53. serum urea levels [ Time Frame: 6 months ]
  54. serum urea levels [ Time Frame: 12 months ]
  55. serum urea levels [ Time Frame: 18 months ]
  56. serum urea levels [ Time Frame: 24 months ]
  57. serum urea levels [ Time Frame: upon conversion to MS (maximum 24 months) ]
  58. serum bilirubin levels [ Time Frame: baseline ]
  59. serum bilirubin levels [ Time Frame: 3 months ]
  60. serum bilirubin levels [ Time Frame: 6 months ]
  61. serum bilirubin levels [ Time Frame: 12 months ]
  62. serum bilirubin levels [ Time Frame: 18 months ]
  63. serum bilirubin levels [ Time Frame: 24 months ]
  64. serum bilirubin levels [ Time Frame: upon conversion to MS (maximum 24 months) ]
  65. serum electrolyte panel [ Time Frame: baseline ]
  66. serum electrolyte panel [ Time Frame: 3 months ]
  67. serum electrolyte panel [ Time Frame: 6 months ]
  68. serum electrolyte panel [ Time Frame: 12 months ]
  69. serum electrolyte panel [ Time Frame: 18 months ]
  70. serum electrolyte panel [ Time Frame: 24 months ]
  71. serum electrolyte panel [ Time Frame: upon conversion to MS (maximum 24 months) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 56 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 ....).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01817166


Contacts
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Contact: Eric Thouvenot, MD, PhD +33.(0)4.66.68.32.61 eric.thouvenot@chu-nimes.fr
Contact: Carey M Suehs, PhD +33.(0)4.66.68.67.88 carey.suehs@chu-nimes.fr

Locations
Show Show 33 study locations
Sponsors and Collaborators
Centre Hospitalier Universitaire de Nīmes
Investigators
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Study Director: Eric Thouvennot, MD, PhD Centre Hospitalier Universitaire de Nîmes
Principal Investigator: Eric Thouvenot, MD, PhD Centre Hospitalier Universitaire de Nîmes

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Responsible Party: Centre Hospitalier Universitaire de Nīmes
ClinicalTrials.gov Identifier: NCT01817166    
Other Study ID Numbers: PHRC-N/2012/ET-01
2012-005821-59 ( EudraCT Number )
First Posted: March 22, 2013    Key Record Dates
Last Update Posted: December 10, 2019
Last Verified: December 2019
Keywords provided by Centre Hospitalier Universitaire de Nīmes:
cholecalciferol
vitamin D
immune disease
clinically isolated syndrome
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Cholecalciferol
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Vitamin D
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents