The primary objective of this study is to assess whether the CD4+ T cell compartment displays a less pro-inflammatory profile in patients which are supplemented for the SOLAR study with high doses of vitamin D3 when compared to patients which are…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Difference in distribution of cytokine profile of peripheral CD4+ T
lymphocytes by flowcytometry at Week 48 between treatment arms
Secondary outcome
• Difference in distribution of results from phenotypic analysis of T and B
lymphocyte subsets by flowcytometry at Week 48 and Week 96 between treatment
arms;
• Difference in distribution of results from functional analysis of cytokine
production (flowcytometry and ELISA assays) by T and B lymphocytes at Week 48
and Week 96 between treatment arms;
• Differences in distribution of circulating levels of immune-related
regulatory molecules at Week 48 and 96 between treatment arms;
• Difference in evolution in time of immune-parameters described above between
the treatment arms;
• Correlation of the distribution of results from the analyses above with serum
levels of 25-hydroxyvitamin D in all participants, as are collected in the
SOLAR(IUM) study;
• Difference in distribution of results from the analyses above between
patients from the vitamin D3 supplementation arm which did or did not respond
clinically to vitamin D3 supplementation (i.e. remained relapse free in the
SOLAR trial at week 96/ No signs of disease activity on MRI);
• Difference in distribution of results from the analyses above between
carriers of relevant genetic polymorphisms as are studied in the SOLAR trial,
including MHC class II region (HLA-DRB15*01) and the vitamin D metabolism genes
(VDR and CYP27B1).
Background summary
Multiple Sclerosis (MS) is an inflammatory disease of the central nervous
system (CNS). Naïve T cells are primed in the periphery and mgrate as
auto-reactive T cells to the CNS, where they contribute to an inflammatory
reaction against the myelin sheaths surrounding neurons. A poor vitamin D
status has been associated with an increased risk on developing MS (Ascherio
et al. Lancet Neurol 2010), and with an increased disease activity of MS
(Simpson et al. Ann Neurol 2010; Mowry et al. Ann Neurol 2010; Smolders et al.
Mult Scler 2008). To assess the efficacy of high dose vitamin D3
supplementation as add-on treatment in patients with MS, we designed the SOLAR
trial.
The mechanism by which vitamin D could modulate the disease course of MS is
unknown, but most researchers think that the central involvement of vitamin D
in the regulation of the adaptive immune response plays a critical role in this
association. In experimental research, in vitro and in animal models of MS,
vitamin D appears to be an important promoter of T cell homeostasis (Smolders
et al. J Neuroimmunol 2008). In a cross-sectional study among MS patients, we
found in patients with a poor vitamin D status less functional regulatory T
cells and a Th1/Th2 balance which was more shifted towards Th1 (Smolders et al.
PLoS One 2009). A phase 1/2 study (Burton et al. Neurology 2010) and a pilot
study (Smolders et al. PLoS One 2010) suggested that supplementation of high
doses of vitamin D could shift the T cell compartment in a less
pro-inflammatory direction.
Study objective
The primary objective of this study is to assess whether the CD4+ T cell
compartment displays a less pro-inflammatory profile in patients which are
supplemented for the SOLAR study with high doses of vitamin D3 when compared to
patients which are supplemented for the SOLAR study with placebo.
Study design
This is a blinded observational study among participants of the SOLAR study.
Participants of SOLAR are randomized over 2 treatment arms: either 96-weeks
supplementation of high doses of vitamin D (4 weeks 7.000 IU/d; 92 weeks 14.000
IU/d), or 96 weeks supplementation of placebo. The peripheral immune
compartment will be assessed at week 0, week 48, and week 96. After the last
analysis of the last patient, the database will be locked and de-blinding will
occur. The difference in distribution of immune parameters between the groups
at week 48 and 96 will be assessed.
Study burden and risks
At given time points, blood is drawn from the participants for de SOLAR trial.
For the SOLAR(IUM) study, a total volume of 10 mL will be added to this
sampling at given time points (week 0, 48, and 96). There is no need for
additional sampling. The risk of this addition for the wellbeing of participant
is negligibly small. The risks of blood withdrawal are a transient vasovagal
collaps ('fainting'), and/or getting a local haematoma.
Postbus 616
6200 MD Maastricht
NL
Postbus 616
6200 MD Maastricht
NL
Listed location countries
Age
Inclusion criteria
In short, the only inclusion criteria are: i) matching the inclusion criteria of SOLAR, ii) willing to provide additional informed consent for the SOLAR(IUM) study. The inclusion most prominent criteria of SOLAR are:
• Males and females between 18 and 50 years of age.
• Diagnosis of a relapsing-remitting form of MS, according to the revised McDonald criteria 2005
• Brain and/or spinal MRI with findings typical of MS.
• A first clinical event occurring within 5 years prior to Screening.
• Disease activity characterized by: at least one MS lesion within the 12 months prior to Screening, or ne or more Gd-enhancing MRI lesions within the 12 months prior to Screening.
• EDSS score <= 4.0 at Screening.
• Currently and for the first time treated with interferon-beta-1a (tiw) s.c., and having received this treatment for a minimum of 90 days and for not longer than 12 months before baseline visit (including titration period).
• Willingness and ability to comply with the protocol for the duration of the trial.
• Written informed consent given prior to any trial-related procedure not part of the normal medical practice.
Exclusion criteria
Te only exclusion criterion of SOLAR(IUM) is matching any exclusion criterium of SOLAR. The most prominent exclusion criteria of SOLAR are:
• Pregnancy and lactation period
• Any disease other than MS that could better explain signs and symptoms.
• Complete transverse myelitis or bilateral optic neuritis.
• Currently receiving or use at any time of monoclonal antibodies, mitoxantrone, cytotoxic or immunosuppressive therapy.
• Use of any cytokine or anti-cytokine therapy, intravenous immunoglobulin, plasmapheresis, or any investigational drug or experimental procedure within 12 months prior to Screening.
• Use of oral or systemic corticosteroids or ACTH within 30 days prior to the SD1 visit.
• Have experienced a relapse within 30 days before the SD1 visit
• Have abnormalities of Vitamin D related hormonal system other than low dietary intake or decreased sun exposure, i.e. primary hyperparathyroidism or granulomatous disorders.
• Have an urine calcium/creatinine (mmol/mmol) ratio greater than 1.0 or hypercalcaemia (11 mg/100cc (5.5 mEq./l.).
• Are taking medications that influence Vitamin D metabolism other than corticosteroids, e.g., phenytoin, barbiturates, thiazide diuretics and cardiac glycosides.
• Are taking more than 400 IU (10 µg) of Vitamin D supplement daily.
• Have conditions with increased susceptibility to hypercalcaemia, e.g., known arrhythmia or heart disease, treatment with Digitalis, or Hydrochlorothiazide and those who suffer from nephrolithiasis.
• Have inadequate liver function, defined by alanine aminotransferase (ALT) > 3 times upper limit of normal (ULN), aspartate aminotransferase (AST) > 3 times upper limit of normal (ULN)or alkaline phosphatase > 2.5 times ULN, or total bilirubin > 1.5 times ULN, if associated with any elevation of ALT or alkaline phosphatase
• Moderate to severe renal impairment
• Inadequate bone marrow reserve, defined by a WBC count < 0.5 times the lower limit of normal.
• History or presence of serious or acute heart disease
• History or presence of severe depression, history of suicide attempt, or current suicidal ideation.
• Epilepsy or seizures not adequately controlled by treatment.
• Current or past (within the last 2 years) alcohol or drug abuse.
• Any major medical or psychiatric illness (such as psychosis, bipolar disorder) that in the opinion of the Investigator could create undue risk to the subject or could affect adherence with the trial protocol.
• Known contra-indication to treatment with vitamin D (according to SPC)
• Known hypersensitivity to IFN or its excipient(s) (according to SPC).
• Known hypersensitivity to gadolinium.
• Any other condition that would prevent the subject from undergoing an MRI scan.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL35094.096.10 |