Please select the eligibility criteria that correspond to the clinical trial below.
Title: A One Year Prospective, Randomized, Double Blind Interventional Study to Assess Tolerability, Quality of Life and Immunomodulation With Interferon Beta Combined With Vitamin D in Patients With Relapsing Remitting Multiple Sclerosis
Brief Summary: The investigators hypothesize that vitamin D supplementation may ameliorate interferon beta-induced flu-like symptoms, owing to reduced release and activity of the cytokines that are in correlation with this adverse event. Vitamin D supplementation may also positively affect injection site reactions due to its immunomodulatory effects. Vitamin D may also augment the therapeutic efficacy of interferon beta among multiple sclerosis (MS) patients. Vitamin D intake may influence melatonin levels of MS patients as they share the same nuclear receptor.


Options:
A: Inclusion Criteria:

* Diagnosis of a relapsing-remitting form of MS
* Brain and/or spinal MRI with findings typical of MS
* A first clinical event prior to Screening.
* Disease activity
* Expanded Disability Status Scale (EDSS) score of less than, or equal to 4.0 at Screening.
* Currently treated with interferon-beta-1a 44mg (tiw) sc
* Willingness and ability to comply with the protocol
* Written informed consent

Exclusion Criteria:

* 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 (excluding systemic steroids and adrenocorticotrophic hormone \[ACTH\]), B cell modulating therapies (e.g. RituxiMab or BelimuMab), total lymphoid irradiation or bone marrow transplantation.
* Use of any cytokine other than interferon or anti-cytokine therapy, intravenous immunoglobulin, plasmapheresis, or any investigational drug or experimental procedure
* Use of oral or systemic corticosteroids or ACTH
* 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
* Are taking medications that influence Vitamin D metabolism other than corticosteroids, e.g., phenytoin, barbiturates, thiazide diuretics and cardiac glycosides.
* Are taking more than 1000 IU (25 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
* Moderate to severe renal impairment
* Inadequate bone marrow reserve
* History or presence of serious or acute heart disease such as uncontrolled cardiac dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled congestive heart failure (NYHA class 3 or 4).
* 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 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
* Known hypersensitivity to interferon or its excipient(s)
* Known hypersensitivity to gadolinium.
* Any other condition that would prevent the subject from undergoing an MRI scan.
* Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such.
* Positive HIV, hepatitis C, or hepatitis B (HBsAg and HBc antibody) serology (test performed at screening).
* Legal incapacity or limited legal capacity.
* Another current autoimmune disease, except diabetes.
* Have experienced a relapse within 30 days.
B: Inclusion Criteria:

* age 18 to 55 years
* remitting-relapsing multiple sclerosis according to McDonald criteria who fulfill the reimbursement criteria for interferon-beta and have used interferon-beta-1b for at least one month
* EDSS (expanded disability statsu scale) ≤ 5
* no neutralising antibodies to INFB as measured by indirect MxA test
* prepared and considered to follow the protocol
* using appropriate contraceptive methods (women of childbearing potential)
* has given informed consent

Exclusion Criteria:

* serum calcium \>2.6 mmol/L
* serum 25(OH)D2 (kalsidiol) \> 85 nmol/L
* presence of primary hyperparathyroidism (serum intact PTH, parathyroid hormone)\>65 ng/L)
* pregnancy or unwillingness to use contraception
* alcohol or drug abuse
* use of glucocorticoid treatment other than intravenous methylprednisolone for treatment of relapses
* current use of other immunomodulatory therapy than interferon-beta-1b
* known allergy to cholecalciferol or arachis oil (peanuts)
* therapy with digitalis, calcitonin or active vitamin D3 analogues during the previous 12 months or multivitamins containing vitamin D during previous two weeks preceding study entry
* any condition predisposing to hypercalcaemia (such as any type of cancer)
* sarcoidosis
* nephrolithiasis or renal insufficiency, serum creatinine above 1.5 times the normal upper reference limit
* significant hypertension (Blood Pressure \<180/110 mmHg)
* hyperthyroidism, or hypothyroidism in the year before the study began
* a history of nephrolithiasis during the previous five years
* cardiac insufficiency or significant cardiac dysrhythmia
* unstable or advanced ischaemic heart disease
* has suffered a major depression
C: Inclusion Criteria: To be eligible for inclusion, each subject must meet each of the following criteria at Screening (Visit 1) and must continue to fulfil these criteria at Baseline (Visit 2).

* CIS: Patients with a clinically isolated syndrome with onset relapse within the previous three months and two or more than two asymptomatic T2 lesions on MRI brain scan.
* Aged 18-55yrs.
* Not receiving any disease modifying therapy.

Exclusion Criteria:

* Patients in whom any disease other than demyelination could explain their signs and symptoms.
* Participants with known disease of the parathyroids, a history of vitamin D intolerance, sarcoidosis, a history of hypercalcaemia of any cause.
* Participants with a baseline abnormality in serum urea, creatinine, calcium, parathormone.
* Participants on thiazide diuretics (hypercalcaemia risk).
* Patients with occurrence of a relapse less than six weeks prior to entry to study.
* Previous treatment with beta-interferons or glatiramer acetate or steroids in the last three months.
* Any previous treatment with mitoxantrone or other immunosuppressant.
* Participants already taking supplemental vitamin D.
D: Inclusion Criteria:

* Male and female patients with a diagnosis of RRMS according to the McDonald criteria (2005)
* At least 18 years of age
* Patients are treated with IFN-beta for RRMS. The decision to treat with IFN beta will be independent from this study protocol.
* Patients will be either newly diagnosed, who are going to start IFN beta therapy for the first time or RRMS patients who suffer from FLS while being treated with IFN beta.
* Insufficient blood levels of 25-hydroxy-vitamin D (below 75nmol/l according to current definitions.
* EDSS score up to 7
* Willing and able to give informed consent

Exclusion Criteria:

* Patients having abnormalities of vitamin D related hormonal system other than low dietary intake or decreased sun exposure will be excluded. Namely, malabsorption \[Celiac, Whipple, Inflammatory bowl disease, Intestinal bypass surgery, Short bowel syndrome, Cirrhosis, Nephrotic syndrome, Hyperthyroidism, Renal failure \[creatinine clearance of less than 40 ml/min\], Rickets, Hypoparathyroidism, Hypercalcemia at baseline, known malignancy, granulomatous disorders (Sarcoidosis, Tuberculosis, Silicosis) and Lymphomas.
* Patients who take medications that influence vitamin D metabolism, other than corticosteroids, will be also excluded. Namely, Orlistat, Anticonvulsants \[Phenobarbital, Primidone, Phenytoin\], Rifampin, Isoniazide, ketoconazole, 5FU and Leucovorin
* Patients with conditions with increased susceptibility to hypercalcemia will be excluded too: known arrhythmia or heart disease, treatment with Digitalis, or Hydrochlorothiazide.and those who suffer from nephrolithiasis.
* Other Central Nervous System disorders than RRMS
* Psychiatric disorders such as psychosis, bipolar disorder or substance abuse
* Pregnancy
* Contra-indication to treatment with IFN-beta

Answer: D