Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase I/II Dose-Escalation Trial of Vitamin D3 With Calcium Supplementation in Patients With Multiple Sclerosis
Brief Summary: Vitamin D likely plays a role in the geography of Multiple Sclerosis (MS), and patients at risk and with MS have relatively low Vitamin D levels compared to their normal counterparts.

This trial examines the safety of high dose oral Vitamin D3 titrated up to a maximum of 40,000 IU per day over a 12 month period. Fifty patients matched for MS and non-MS characteristics will be divided into two groups: one group receiving the high dose Vitamin D regimen, and the other restricted to a maximum of 4000 IU per day. The hypothesis is that patients with MS can tolerate seemingly high doses of Vitamin D3 without adverse events and/or calcium-related abnormalities. It is also hypothesized that those receiving the higher doses will demonstrate improved relapse and disability status compared to controls, and that the treatment group will show improved markers of bone health and immune indicators of reduced inflammation.


Options:
A: Inclusion Criteria:

* Clinically definite MS
* Age 18-55
* EDSS 0-6.5

Exclusion Criteria:

* EDSS =\> 7.0
* Current Vitamin D3 use \>4000 IU/d
* Baseline (25(OH)D) level \<20 mmol/L (frank deficiency) and \>150 mmol/L
* Pregnancy or inability/unwillingness to use contraception
* History of cardiac arrhythmia
* History of renal disease and nephrolithiasis
* History of granulomatous disease or lymphoma
* Relapse activity or steroid use in the past 60 days
B: Inclusion Criteria:

* Age 18 to 50 years
* EDSS \< 4.0 (able to walk without rest some 500 m)
* Women have to be premenopausal
* MS according to the McDonald criteria; prepared and considered able to follow the protocol; using appropriate contraceptive methods (women of childbearing potential)
* Having given written informed consent.

Exclusion Criteria:

* Pregnancy or unwillingness to use contraception; alcohol or drug abuse
* Use of glucocorticoid treatment other than intravenous methylprednisolone for treatment of relapses
* Known allergy to cholecalciferol or arachis oil (peanuts)
* Therapy with digitalis, calcitonin, active vitamin D3 analogues, fluoride, or bisphosphonates during the previous 12 months
* Any condition predisposing to hypercalcaemia
* Nephrolithiasis or renal insufficiency
* Presence of primary hyperparathyroidism, hyperthyroidism, or hypothyroidism in the year before the study began; a history of nephrolithiasis during the previous five years.
C: 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.
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: A