title: A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.
abstract: OBJECTIVE
  Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively.
  
  
  METHODS
  An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score.
  
  
  RESULTS
  Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413 nmol/L, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls.
  
  
  CONCLUSIONS
  High-dose vitamin D (approximately 10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects.
  
  
  METHODS
  This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation. The trial, however, lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures (relapses and Expanded Disability Status Scale scores), providing only Class level IV evidence for these outcomes.
authors.affiliation: Division of Neurology, St. Michael's Hospital, Toronto, Canada. jodie.burton@albertahealthservices.ca
authors.forename: J M
authors.initials: JM
authors.lastname: Burton
authors.forename: S
authors.initials: S
authors.lastname: Kimball
authors.forename: R
authors.initials: R
authors.lastname: Vieth
authors.forename: A
authors.initials: A
authors.lastname: Bar-Or
authors.forename: H-M
authors.initials: HM
authors.lastname: Dosch
authors.forename: R
authors.initials: R
authors.lastname: Cheung
authors.forename: D
authors.initials: D
authors.lastname: Gagne
authors.forename: C
authors.initials: C
authors.lastname: D'Souza
authors.forename: M
authors.initials: M
authors.lastname: Ursell
authors.forename: P
authors.initials: P
authors.lastname: O'Connor
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002118:Calcium / Q000008:administration & dosage* / Q000652:urine; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000178:diet therapy* / Q000378:metabolism*; D011446:Prospective Studies; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014807:Vitamin D / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood; D014815:Vitamins / Q000008:administration & dosage* / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D019715:Tissue Inhibitor of Metalloproteinase-1; D014815:Vitamins; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D020780:Matrix Metalloproteinase 9; D002118:Calcium