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Vitamin D3 and the Stress-axis in MS

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ClinicalTrials.gov Identifier: NCT02096133
Recruitment Status : Terminated (difficulties with inclusion)
First Posted : March 26, 2014
Last Update Posted : January 25, 2017
Sponsor:
Information provided by (Responsible Party):
Raymond Hupperts, Academic MS Center Limburg

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.

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Cholecalciferol Other: Placebo comparator Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 54 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Regulation of the Stress-axis by Vitamin D3 in Subjects With Multiple Sclerosis; a Double-blinded, Randomized, Placebo-controlled Study
Study Start Date : October 13, 2014
Actual Primary Completion Date : November 7, 2016
Actual Study Completion Date : November 7, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cholecalciferol
Patients receive 1dd 100ug vitamin D3 (drops) for 16 weeks
Drug: Cholecalciferol
Vitamin D3 solution
Other Name: Vigantol Oil

Placebo Comparator: Placebo comparator
placebo drops during 16 weeks
Other: Placebo comparator
Placebo comparator




Primary Outcome Measures :
  1. The area under the curve (AUC) of the cortisol day curve [ Time Frame: At baseline and after 16 weeks of supplementation. ]
    This number is constructed by combining the saliva cortisol levels at awakening, 11:00, 15:00, 20:00, and 22:00 hours (5 time-points).


Secondary Outcome Measures :
  1. The slope of the cortisol day-curve [ Time Frame: At baseline and after 16 weeks of supplementation ]
    The slope of the day-curve is the slope of the decrease of saliva cortisol measured throughout the cortisol day curve

  2. The cortisol awakening response [ Time Frame: At baseline and after 16 weeks of supplementation ]
    The awakening response is described by the rise in saliva cortisol from awakening to 60 minutes after awakening with respectively measurements at awakening, 15 minutes, 30 minutes, 45 minutes and 60 minutes (5 time-points).

  3. Clinical outcomes on depression [ Time Frame: At baseline and after 16 weeks of supplementation ]
    The clinical outcomes on depression will be measured by the depression sub-score of HADS and the FSSS fatigue score.

  4. Efficacy of supplementation [ Time Frame: At baseline and after 16 weeks of supplementation. Side effects will also be checked at 8 weeks of supplementation. ]
    To measure efficacy 25(OH)D levels will be measured.

  5. Side effects [ Time Frame: At baseline, after 8 and after 16 weeks ]
    Side effects will be measured after 8 and 16 weeks of treatment. Serum levels of calcium, albumin and creatinine will be determined, as well as calcium and creatinine levels in urine.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02096133


Locations
Netherlands
Canisius Wilhelmina Ziekenhuis
Nijmegen, Netherlands
Academic MS Center Limburg, Orbis Medical Center
Sittard-Geleen, Netherlands, 6162 BG
Sponsors and Collaborators
Academic MS Center Limburg
Investigators
Principal Investigator: Raymond Hupperts, MD, PhD Academic MS Center Limburg, Orbis MC

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Raymond Hupperts, Prof. R.M.M. Hupperts, MD, PhD, neurologist, Academic MS Center Limburg
ClinicalTrials.gov Identifier: NCT02096133     History of Changes
Other Study ID Numbers: EMR200109_635
2014-000728-97 ( EudraCT Number )
First Posted: March 26, 2014    Key Record Dates
Last Update Posted: January 25, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Raymond Hupperts, Academic MS Center Limburg:
Multiple sclerosis, vitamin D, HPA-axis, cortisol

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Vitamins
Vitamin D
Ergocalciferols
Cholecalciferol
Micronutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents