Investigating the Effects of Hydroxyvitamin D3 on Multiple Sclerosis

Phase 4

• Conditions: Adult ALL; Multiple Sclerosis, Relapsing-Remitting; Vitamin D3 Deficiency
• Interventions: Dietary Supplement: vitamin D3; Dietary Supplement: 25(OH)D3

• Registration Number: NCT05340985
• Lead Sponsor: Tehran University of Medical Sciences

Brief Summary

Investigating the effects of hydroxyvitamin D3 on clinical, radiologic and immunomodulatory markers in MS patients: A randomized, clinical trial- a pilot study

Detailed Description

Vitamin D deficiency/insufficiency is a risk factor for developing MS and is linked to increased disease activity in those with established disease. Several clinical trials have already been conducted to consider the effect of vitamin D supplementation on clinical outcomes of the disease but the findings were inconsistent.

This paradox may be explained by supplementation dose, trial duration and also an insufficient rise in serum 25-hydroxyvitamin D to be effective on immunomodulatory pathways and consequent clinical outcomes.

Of note, it was revealed that MS patients have a lower rise in serum 25-hydroxyvitamin D \[25(OH)D\] levels compared with healthy controls (HCs), when given the same amount of oral cholecalciferol supplementation.

Cholecalciferol is the main vitamin D supplement that was used in these trials. When vitamin D3 is ingested, it is incorporated into chylomicrons and enters the lymphatic system. The chylomicrons then enter into the bloodstream via the superior cava. Most of the vitamin D is incorporated into the body fat.

Vitamin D3 in the circulation and the vitamin D3 that is slowly released from the body fat into the circulation is converted in the liver to 25(OH)D3, taking approximately 6-8 weeks to achieve a steady state concentration of 25(OH)D3.

The more rapid increase in serum concentrations of 25(OH)D3, by treatment with calcifediol instead of cholecalciferol, may provide an advantage through rapid entry into its target innate and adaptive immune cells, resulting in the paracrine/autocrine production of 1α,25(OH)2D which interacts with the vitamin D receptor (VDR) to modulate immune function.

Study Timeline

• Status Verified: 2022-02
• Study First Submitted: 2022-03-02
• Study First Submitted QC: 2022-04-16
• Last Update Submitted: 2022-04-16
• Study First Posted: 2022-04-22
• Last Update Posted: 2022-04-22
• Study Start: 2022-07
• Primary Completion: 2023-06
• Study Completion: 2023-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 54

Inclusion Criteria

1. MS type: relapsing-remitting MS (RRMS)
2. older than 18 year-old
3. Vitamin D deficiency/insufficiency (25(OH)D<30 ng/ml

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Exclusion Criteria

1. medications or disorders that would affect vitamin D metabolism
2. history of other chronic disorders
3. history of conditions that could lead to high serum calcium levels
4. pulse therapy in the last 3 months
5. history of attack in the last 3 months
6. using corticosteroid in the last 3 months
7. be pregnant

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cholecalciferol	vitamin D3	50 micrograms (2000IU) per day Cholecalciferol for 24 Weeks
25(OH)D3 (Calcifediol)	25(OH)D3	50 micrograms per day 25(OH)D3 or vitamin D hydroxylated for 24 weeks

Primary Outcome Measures

Name	Time	Method
Change in MRI parameters	6 months (baseline and end of 6th month) in each intervention arm	new lesions on T2 weighted images, gadolinium enhancing lesions in T1-weighted images
disability	6 months (baseline and end of 6th month) in each intervention arm	Change in expanded disability status scale (EDSS) according to Kurtzke 1983. The minimum is 0 (no disability) and maximum value is 10 (Death due to MS)- higher scores mean a worse outcome.
changing in brain parameters of Diffusion tensor imaging (DTI)	6 months (baseline and end of 6th month) in each intervention arm	the integrity of white matter (WM) by analyzing WM microstructure through DTI
Number of relapses	6 months (baseline and end of 6th month) in each intervention arm	neurologic symptoms lasting more than 24 hours which occur at least 30 days after the onset of a preceding event
Differential gene expression	6 months (baseline and end of 6th month) in each intervention arm	After six months of 25-hydroxy vitamin D supplementation, the differentially expressed genes (DEGs) in peripheral blood mononuclear cells at the transcriptome level will be considered by RNA-seq
changing in Cognition	6 months (baseline and end of 6th month) in each intervention arm	Changing in cognitive functions by the Minimal Assessment of Cognitive Function in MS (MACFIMS) battery. The lower the score the more disfunction.; MACFIMS is consisting of 7 subtests including: 1. the California Verbal Learning Test second edition (CVLT-II), with the range score: 0-80; 2. the Paced Auditory Serial Addition Test (PASAT), with the range score: 0-16; 3. the Symbol Digit Modalities Test (SDMT), with the range score: 0-110; 4. the Brief Visuospatial Memory Test-Revised (BVMT-R), with the range score: 0-36; 5. the Controlled Oral Word Association Test (COWAT), with the range score: 0-12; 6. the Delis-Kaplan Executive Function System (DKEFS) sorting Test, with the range score: 0- undetermined; 7. the Judgment of Line Orientation Test (JLO), with the range score: 0-30; The higher score in each subtest means the better cognitive function
CD4+ T cell response	6 months (baseline and end of 6th month) in each intervention arm	After six months, changing the balance of Th17 and Tregs subtypes of CD4+ T cells.; Detecting interleukin (IL) 17 -expressing T cells and Tregs expressing T cells by flow cytometry.

Secondary Outcome Measures

Name	Time	Method
changing in quality of life	6 months (baseline and end of 6th month) in each intervention arm	changing in quality of life that determined by the Short Form Health Survey that contains 36-item (Sf36). The score is between 0-100.; The lower the score the more disability. The higher the score the less disability.
needing hospitalization	6 months (baseline and end of 6th month) in each intervention arm	needing hospitalization due to remissions and exacerbations of the disease
effective in rapidly raising circulating levels of 25(OH)D3	6 months (baseline and end of 6th month) in each intervention arm	Serum levels of 25-hydroxy vitamin D (25(OH)D will be measured by High-performance liquid chromatography (HPLC)
changing in the circulating levels of interleukin 17 as a inflammatory marker	6 months (baseline and end of 6th month) in each intervention arm	After six months of calcifediol/or cholecalciferol supplementation, measuring serum levels of IL-17 by enzyme-linked immunoassay (ELIZA) kit.
changing in the levels of interleukin 10 as anti- inflammatory marker	6 months (baseline and end of 6th month) in each intervention arm	After six months of calcifediol/or cholecalciferol supplementation, measuring serum levels of IL-10 by ELIZA kit.
changing in the levels of Tumor Necrosis Factor alpha (TNF-a) as an inflammatory marker related the T-CD4 subsets	6 months (baseline and end of 6th month) in each intervention arm	After six months of calcifediol/or cholecalciferol supplementation, measuring serum levels of TNF-a by ELIZA kit.