title: Effect of Alfacalcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study.
abstract: BACKGROUND
  Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS); however, there is no medication that has been approved specifically to treat MS-related fatigue.
  
  
  OBJECTIVE
  We aimed to evaluate the effect of vitamin D analogue, Alfacalcidol, on MS-related fatigue.
  
  
  METHODS
  This was a randomized, double-blind, parallel group, placebo-controlled trial in patients with clinically definite MS by McDonald criteria conducted in a single university-affiliated medical center in Israel. Randomly selected patients from the Sheba MS Registry computerized database (N=600) were assessed using the self-report Fatigue Severity Scale (FSS). Patients with clinically meaningful fatigue (N=259) were further assessed for trial eligibility, and MS patients with significant fatigue (N=158; 61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) were included in the study and randomized to receive treatment or placebo.
  
  
  METHODS
  Alfacalcidol (1 mcg/d, N=80) or placebo (N=78) was administered for six consecutive months.
  
  
  METHODS
  The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the Fatigue Impact Scale (FIS) score; the cut-off point for improvement was defined as 30% decrease. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated regardless of whether or not they dropped out.
  
  
  RESULTS
  Alfacalcidol decreased the mean relative FIS score as compared with placebo (-41.6% vs. -27.4%, p=0.007, respectively). This advantage was further emphasized when the modified FIS (MFIS) relative change was calculated. Quality of Life (QoL) improved in Alfacalcidol-treated patients as compared with placebo in the RAYS psychological (p=0.033) and social (p=0.043) sub-scales. The Alfacalcidol-treated group had reduced number of relapses (p=0.006) and higher proportion of relapse-free patients (p=0.007). Reduction of relapses by Alfacalcidol became significant at 4 months of treatment, was sustained at 6 months and decayed 2 months after drug discontinuation. Alfacalcidol treatment was safe and no serious adverse events were recorded.
  
  
  CONCLUSIONS
  Alfacalcidol is a safe and effective treatment strategy to decrease fatigue and improve QoL in patients with MS.
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, 52621, Israel anat.achiron@sheba.health.gov.il.
authors.forename: Anat
authors.initials: A
authors.lastname: Achiron
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Givon
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Magalashvili
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Mark
authors.initials: M
authors.lastname: Dolev
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Liraz Zaltzman
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Kalron
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Stern
authors.affiliation: Teva Pharmaceutical Industries, Israel.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Mazor
authors.affiliation: Teva Pharmaceutical Industries, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Ladkani
authors.affiliation: Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Barak
mesh_terms: D000328:Adult; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D005221:Fatigue / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D006801:Humans; D006887:Hydroxycholecalciferols / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy*; D011788:Quality of Life; D012008:Recurrence; D012042:Registries; D016896:Treatment Outcome
chemical_list: D050071:Bone Density Conservation Agents; D006887:Hydroxycholecalciferols; C008088:alfacalcidol
keywords: Alfacalcidol; Multiple sclerosis; Quality of Life; clinical trial; fatigue