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

• ClinicalTrials.gov Identifier: NCT01817166
• Recruitment Status: Completed
• First Posted: March 22, 2013
• Last Update Posted: May 6, 2023
• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Information provided by (Responsible Party): Centre Hospitalier Universitaire de Nīmes

Study Description

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual 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
• Actual Primary Completion Date: January 4, 2023
• Actual Study Completion Date: January 4, 2023

Arms and Interventions

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.

Outcome Measures

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) ]

Eligibility Criteria

• 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 ....).

Contacts and Locations

Locations

France

CHU d'Amiens - Hôpital Nord

Amiens Cedex 1, France, 80054

CHU de Lyon - Hôpital Pierre Wertheimer

Bron, France, 69677

CHU de Caen - Hôpital Côte de Nacre

Caen Cedex 9, France, 14033

CHU de Clermont Ferrand - Hôpital Gabriel-Montpied

Clermont Ferrand, France, 63003

CH Sud Francilien

Corbeil-Essonnes, France, 91100

Clinique des Cèdres - Capio

Cornebarrieu, France, 31700

CHU de Dijon

Dijon, France, 21079

CHU de Martinique - Hôpital Pierre Zobda-Quitman

Fort-de-France, France, 97261

CHU de Grenoble - Hôpital A Michallon

Grenoble, France, 38043

CHRU de Lille - Hôpital Roger Salengro

Lille, France, 59037

CHU de Limoges - Hôpital Dupuytren

Limoges, France, 87042

Groupe Hospitalier de l'Institut Catholique de Lille

Lomme Cedex, France, 59462

CHU de Montpellier - Hôpital Gui de Chauliac

Montpellier, France, 34295

CHU de Nancy - Hôpital Central

Nancy, France, 54035

CHU de Nantes - Hôtel-Dieu

Nantes, France, 44093

CHU de Nice - Hôpital Pasteur

Nice, France, 06002

CHU de Nîmes - Hôpital Universitaire Carémeau

Nîmes Cedex 9, France, 30029

APHP - Hôpital Saint-Antoine

Paris Cedex 12, France, 75571

MAILLART Elisabeth - La Pitié Salpétrière

Paris, France, 75013

Fondation Ophtalmologique Adolphe Rothschild

Paris, France, 75019

CH de Pau

Pau, France, 64000

CH de Perpignan - Hôpital Saint Jean

Perpignan, France, 66046

CH de Cornouaille - Site Quimper - Hôpital Laennec

Quimper, France, 29107

CHU de Reims - Hôpital Maison Blanche

Reims, France, 51092

CHU de Rennes - Hôpital PontChaillou

Rennes, France, 35033

CHU de Rouen - Hôpital Charles Nicolle

Rouen, France, 76031

CH de Poissy - Saint-Germain-en-Laye

Saint-Germain-en-Laye, France, 78100

CH de Saumur

Saumur Cedex, France, 49403

CHRU de Strasbourg - Hôpital Civil

Strasbourg Cedex, France, 67091

CHRU de Toulouse - Hôpital Purpan

Toulouse Cedex 9, France, 31059

CHRU de Tours - Hôpital Bretonneau

Tours, France, 37044

CH de Versailles - Hôpital Mignot

Versailles, France, 78000

CH de Vichy - Jacques Larin

Vichy, France, 03207

Sponsors and Collaborators

Centre Hospitalier Universitaire de Nīmes

Investigators

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

More Information

• 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
• Last Update Posted: May 6, 2023
• Last Verified: May 2023

Keywords provided by Centre Hospitalier Universitaire de Nīmes:

cholecalciferol; vitamin D; immune disease; clinically isolated syndrome

Additional relevant MeSH terms:

Vitamin D; Multiple Sclerosis; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Cholecalciferol; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents