Clinical trial NCT02096133: Vitamin D3 and the Stress-axis in MS
Official title: Regulation of the Stress-axis by Vitamin D3 in Subjects With Multiple Sclerosis; a Double-blinded, Randomized, Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Multiple Sclerosis
Keywords: Multiple sclerosis, vitamin D, HPA-axis, cortisol
Lead sponsor: Academic MS Center Limburg
Sponsor class: OTHER
First posted: 2014-03-26
Enrollment: 54
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: Patients with multiple sclerosis (MS) have an increased risk of developing a major depression. The investigators observed a protective effect of high vitamin D levels on the risk of depression in MS. This might be driven by the effect of vitamin D on the stress-axis. Therefore, the main goal of the present study is to assess whether high dose vitamin D supplementation results in a suppression of the stress-axis, as measured by decreased levels of cortisol.

Detailed description: The lifetime incidence of a major depression in Multiple Sclerosis (MS) is 50%. (Patten et al. Neurology 2003; 61(11):1524-7) Our group reported a negative correlation between vitamin D status and depression score of the Hospital Anxiety and Depression Scale (HADS) in a cross-sectional dataset of Dutch MS patients. (Knippenberg et al. Acta Neurol Scand 2011; 124(3):171-5) This suggests an interaction between vitamin D and biological mechanisms affecting susceptibility to depression. Currently, we have two main hypotheses: 1) Vitamin D regulates the hypothalamic stress axis in MS. Based on our findings that cortisol releasing hormone (CRH)-positive hypothalamic neurons in the brains of MS patients stained positive for the vitamin D receptor (VDR) and 1,25(OH)2D-24-hydroxylase (24-OHase). (smolders et al. J Neuropathol Exp Neurol 2013;72(2):91-105) 2) Vitamin D affects T cell cytokine profile and hereby the odds of developing depression. Also in non-MS depressed patients increased levels of pro-inflammatory cytokines are detected (Maes et al. Metab Brain Dis 2009; 24: 27-53). Vitamin D3 has shown to be a potent promotor of T cell regulation both in vitro and in vivo. (Smolders et al. J Neuroimmunol 2008;194:7-17 and Smolders et al. PLoS One 2010;5:e15235) The main goal of this study is to assess whether supplementation of high doses vitamin D3 results in a suppression of saliva cortisol day-curves in subjects with multiple sclerosis, and we will explore whether the pro-inflammatory cytokine profile of T lymphocytes is regulated.

Eligibility criteria: Inclusion Criteria:

* Female
* Relapsing Remitting MS
* At start of study \> 6 weeks in clinical remission of disease
* Age \> 18 years.
* Premenopausal
* Treated with either no immune-modulating treatment, or the currently registered MS modulating treatments: Interferon beta 1a (Rebif®), Interferon Beta 1b (Betaferon® or Avonex®), Glatiramer Acetate (Copaxone®), dimethylfumarate (Tecfidera®), teriflunomide (Aubagio®)) or fingolimod (Gilenya®).

Exclusion Criteria:

* Any contraindication to vitamin D according to Summary of Product Characteristics: Hypercalcaemia, hypervitaminosis D, nephrolithiasis, diseases or conditions resulting in hypercalcaemia and/or hypercalciuria (incl. primary hyperparathyroidism), severe renal impairment .
* Use of dexamethasone or other systemic glucocorticosteroids \<2 months prior to first study visit
* Supplementation of \>=1000 IU/d (25µg) vitamin D2 or D3
* Medical history of disturbed vitamin D/ calcium metabolism other than low intake
* Present clinical (major)depression
* Present treatment with anti-depressants, benzodiazepines, or neuroleptics.
* Treatment with high-dose dexamethasone for MS exacerbation during study.
* Pregnancy or the intention to become pregnant during the study period.

Primary outcomes:
measure: The area under the curve (AUC) of the cortisol day curve
timeFrame: At baseline and after 16 weeks of supplementation.
Secondary outcomes:
measure: The slope of the cortisol day-curve
timeFrame: At baseline and after 16 weeks of supplementation
measure: The cortisol awakening response
timeFrame: At baseline and after 16 weeks of supplementation
measure: Clinical outcomes on depression
timeFrame: At baseline and after 16 weeks of supplementation
measure: Efficacy of supplementation
timeFrame: At baseline and after 16 weeks of supplementation. Side effects will also be checked at 8 weeks of supplementation.
measure: Side effects
timeFrame: At baseline, after 8 and after 16 weeks
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
city: Sittard-Geleen
country: Netherlands
facility: Academic MS Center Limburg, Orbis Medical Center
Study officials:
affiliation: Academic MS Center Limburg, Orbis MC
name: Raymond Hupperts, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rolf L, Damoiseaux J, Huitinga I, Kimenai D, van den Ouweland J, Hupperts R, Smolders J. Stress-Axis Regulation by Vitamin D3 in Multiple Sclerosis. Front Neurol. 2018 Apr 26;9:263. doi: 10.3389/fneur.2018.00263. eCollection 2018.