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

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.

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

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis; Clinically Isolated Syndrome
• Intervention / Treatment: Dietary supplement: 5000IU vitamin D; Dietary supplement: 10000IU vitamin D; Other: Placebo

Detailed Description

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:

1. 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
2. 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.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Ireland
  • Dublin 4
    • Dublin, Dublin 4, Ireland
      • St Vincent's University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum calcium	a measure of calcium homeostasis	Every 4 weeks for 24 weeks
Number of participants with adverse events as a measure of safety and tolerability of vitamin D in doses of 5,000IU and 10,000IU daily		four weekly assessments over 24 weeks
serum urea	a measure of renal function	4 weekly over 24 weeks
serum creatinine	a measure of renal function	4 weekly over 24 weeks
serum 25(OH)D levels	a measure of response to oral dosing and adherence to therapy.	4 weekly over 24 weeks
serum parathormone (iPTH)	a measure of parathyroid function	4 weekly over 24 weeks

Collaborators and Investigators

• Sponsor: University College Dublin
• Collaborators: St Vincent's University Hospital, Ireland; University of Dublin, Trinity College
• Investigators: Principal Investigator: Michael Hutchinson, MB, FRCP, St Vincent's University Hospital

Publications and helpful links

General Publications

• O'Connell K, Kelly S, Kinsella K, Jordan S, Kenny O, Murphy D, Heffernan E, O'Laoide R, O'Shea D, McKenna C, Cassidy L, Fletcher J, Walsh C, Brady J, McGuigan C, Tubridy N, Hutchinson M. Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo-controlled trial. Trials. 2013 Aug 27;14:272. doi: 10.1186/1745-6215-14-272.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2012
• Primary Completion (Actual): June 5, 2015
• Study Completion (Actual): June 5, 2016

Study Registration Dates

• First Submitted: November 8, 2012
• First Submitted That Met QC Criteria: November 19, 2012
• First Posted (Estimate): November 20, 2012

Study Record Updates

• Last Update Posted (Actual): May 3, 2017
• Last Update Submitted That Met QC Criteria: May 1, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Vitamin D; Clinically isolated syndrome; Multiple sclerosis; Cytokine; Immune response; CD4 T cell subsets
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Disease; Multiple Sclerosis; Sclerosis; Syndrome; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: 2012CIS/VD/SVUH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: all demographic details and outcome measures may be obtained directly from the PI by e-mail

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No