Dose-related Effects of Vitamin D3 on Immune Responses in Patients With Clinically Isolated Syndrome

Study Overview
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Brief Summary
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The primary purpose of this study is to assess the immune response to vitamin D supplementation at two doses (5,000 IU and 10,000 IU daily) in both healthy controls and patients with clinically isolated syndrome compared to placebo. Secondary endpoints include (1) disease outcome in the clinically isolated syndrome in terms of clinical relapses and evidence of new lesions on MRI (McDonald's MS), 2) Safety of doses used

Detailed Description
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Primary endpoint: To determine the effects of vitamin D supplementation at two doses a) 5,000 IU daily b) 10,000 IU daily compared to c) placebo a 24 weeks period on the change from baseline in frequency of CD4 T cell subsets and cytokine responses by peripheral blood mononuclear cells in 1) patients with the clinically isolated syndrome. 2) healthy control participants. Secondary endpoints: To determine whether there is a dose response effect of supplementation using 5,000 IU and 10,000 IU of vitamin D versus placebo over 24 weeks on the change from baseline in the frequency of CD4 T cell subsets and cytokine responses by PBMC in 1) patients with the clinically isolated syndrome (CIS) 2) healthy control participants To establish whether there is a clinical response to vitamin D measured by a) change in the number of T2 lesions and Gadolinium enhancing lesions on MRI scanning at 24 weeks compared to baseline b) reduction in relapses over 24 weeks in treated (both 5,000 IU and 10,000 IU) CIS patients versus CIS patients receiving placebo.

Official Title
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Dose-related Effects of Vitamin D3 on Immune Responses in Patients With Clinically Isolated Syndrome and Healthy Control Participants. An Exploratory Double Blind Placebo Randomised Controlled Study.

Conditions
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Clinically Isolated Syndrome, Multiple Sclerosis

Intervention / Treatment
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* Dietary Supplement: 5000IU vitamin D
* Dietary Supplement: 10000IU vitamin D
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double-blind, dose ranging, two doses of vitamin D, randomised parallel groups with placebo arms in clinically isolated syndrome and heathy control participants
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Healthy control - 5,000 IU vitamin D<br>13 healthy controls will be administered 5,000 IU vitamin D. Primary outcome and safety outcome measures will be assessed. | Dietary Supplement: 5000IU vitamin D<br>* Vigantol Oil<br>* Other names: Vigantol Oil;|
| Active Comparator: Healthy control - 10,000 IU vitamin D<br>13 healthy controls will be administered 10,000 IU vitamin D. Primary outcome and safety outcome measures will be assessed. | Dietary Supplement: 10000IU vitamin D<br>* Vigantol Oil<br>* Other names: Vigantol Oil;|
| Placebo Comparator: CIS - placebo<br>15 patients will be administered placebo and all outcome measures will be assessed. | Other: Placebo<br>* Placebo Oil<br>* Other names: Placebo Oil;|
| Active Comparator: CIS - 5,000 IU vitamin D<br>15 patients will be administered 5,000 IU vitamin D and all outcomes will be assessed. | Dietary Supplement: 5000IU vitamin D<br>* Vigantol Oil<br>* Other names: Vigantol Oil;|
| Active Comparator: CIS - 10,000 IU vitamin D<br>15 patients will be administered 10,000 IU of vitamin D and all outcome measures assessed. | Dietary Supplement: 10000IU vitamin D<br>* Vigantol Oil<br>* Other names: Vigantol Oil;|
| Placebo Comparator: Healthy control - placebo<br>13 control participants who will be administered placebo. These will be assessed for the primary outcome and safety outcomes only. | Other: Placebo<br>* Placebo Oil<br>* Other names: Placebo Oil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effects of two doses of vitamin D and placebo therapy on the change in the frequency of CD4 T cell subsets and cytokine responses of PBMC over 24 weeks of therapy from baseline. | A number of measures will be examined in particular IL-10 production and the frequency of Th17 cells. | This outcome measure will be assessed at baseline and at 24 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of new T2 and gadolinium enhancing lesions compared to baseline amongst the study group. | The MRI out-come measure will assess the a) number of Gadolinium enhancing lesions b) the number of new and enlarging T2 lesions c) the combined unique lesion count (new and enlarging T2 lesions plus Gadolinium enhancing lesions) after 24 weeks of therapy in the three arms, 5000IU, 10,000IU vitamin D and placebo . Mean and median new T2 and gadolinium-enhancing lesions at 24 weeks (end of the trial) will be compared for each treatment allocation group. In addition the mean and median number of new T2 lesions plus gadolinium enhancing lesions in all the CIS patients on vitamin D will be compared to the mean and median in the placebo group. | Baseline and 24 weeks | 
| Relapse occurrence in the CIS patients during 24 weeks of the trial | Relapse occurrence in the CIS patients during 24 weeks of the trial;(i) annualised relapse rates (ARR), (ii) percentage of patients free from relapses and (iii) time to first relapse will be compared for each treatment allocation group. In addition the same relapse measures will be applied to both vitamin D treated groups combined and compared to those in the placebo group. | At each clinic visit or as the need arises. | 
| The percentage of CIS patients in each treatment arm free from any evidence of disease activity (No relapses, no new T2 lesions, no gadolinium enhancing lesions). |  | At 24 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immune response, Clinically isolated syndrome, Multiple sclerosis, Vitamin D, CD4 T cell subsets, Cytokine