Pharmacokinetics of Vitamin D in Multiple Sclerosis and in Health

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01667796
• Collaborator: University of California, San Francisco (Other), National Multiple Sclerosis Society (Other)
• Enrollment: 57
• Locations: 2
• Arm: 1
• Duration (Months): 40
• Patients Per Site: 28.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This is a pilot study of oral vitamin D supplementation to determine if patients with Multiple Sclerosis (MS) and healthy individuals attain a similar increase in serum 25-hydroxyvitamin D levels. The investigators will also assess whether the immunologic or relevant gene expression response to oral vitamin D supplementation differs in patients with MS and healthy controls.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis, Relapsing-remitting	Dietary Supplement: Vitamin D3	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Pharmacodynamic and Immunologic Effects of Vitamin D Supplementation in Patients With Multiple Sclerosis and Healthy Controls
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vitamin D3 Both those with MS and healthy controls will be given vitamin D3 5000 IU/day by mouth for 90 days.	Dietary Supplement: Vitamin D3

Outcome Measures

Primary Outcome Measures

1. Change in Mean Serum Level of 25-hydroxyvitamin D [Baseline to 90 days]

   Generalized estimating equations (GEE) with an autoregressive with lag one correlation matrix were used to compare the serially-measured serum 25(OH)D levels between MS patients and Healthy Controls (HCs) to take into account repeated measures and within-subject correlations.

Secondary Outcome Measures

1. Change in Percentages of T Cell Subsets (IFNγ+ and IL-17+) [Baseline, 90 days]

   Analyzed the mean percentage change in IFNγ+ and IL-17+ cluster of differentiation 4 (CD4) + cells (post- versus pre- supplementation). This represents a change between two time points (90 days versus baseline).

2. Gene Expression Microarray [90 days]

   We had initially planned to do whole blood gene expression. The experience gained by the laboratory that was to perform this since the original trial was planned was that this measure is too noisy and would not yield meaningful results. Thus, this analysis will no longer be conducted.

3. Change in Cytokine Levels [90 days]

   The original plan had been to measure the change in basic serum cytokine levels (e.g. IL-17, interferon gamma; IL-10; pg/microliter). However, due to emerging data suggesting low utility of these measures, this plan was abandoned.

4. Change in Percentage of B Cells [90 days]

   The change in percentage (day 90-baseline) was originally planned for study. Due to the limited number of patients with samples this plan was abandoned.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Female

• Healthy or multiple sclerosis

• Aged 18 to 60

• Body mass index is between 18 kg/m2 and 30 kg/m2

• Screening 25-hydroxyvitamin D level ≤ 75 nmol/L (30 ng/mL)

• White race

• Non-Hispanic ethnicity

• Willing to use birth control during study

• Willing to not use tanning bed during study

If subject has multiple sclerosis:

• Relapsing-remitting MS, as defined by McDonald 2005 criteria

• Screening Expanded Disability Status Scale score ≤ 3.0

• Using no medication for MS, or taking Copaxone, (glatiramer acetate), interferons, or natalizumab

Exclusion Criteria:

• Pregnant or nursing

• Taking multivitamin & unwilling to remain off it during study

• Taking cod liver oil & unwilling to remain off it during study

• On a fat-restricted diet

• History of renal disease or nephrolithiasis (kidney stones)

• History of liver disease

• Taking thiazide diuretics

• History of hyperthyroidism

• History of infection with Mycobacterium species

• History of sarcoidosis

• History of cancer

• History of cardiac disease

• History of HIV

• History of gastrointestinal disorder

• Taking medications that interfere with gastrointestinal absorption

• Cigarette smoker in past month

• Use of illicit drugs in past month

• Use of steroids in past month

• History of hypercalcemia, and screening serum calcium ≤ 10 mg/dL (UCSF) or ≤ 10.7 mg/dL (Johns Hopkins)

• History of hypercalciuria

• Evidence of anemia (Hgb <11.0 g/dL)

• History of other serious medical conditions

• Taking medications that involve the P450 system or may interact with vitamin D (digoxin, diltiazem, verapamil, cimetidine, heparin, or low-molecular weight heparin)

• Other concerns about safety from the perspective of the treating physician

If subject has MS:

-History of major heat sensitivity (leading to sun-avoidant behaviors)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143
2	Johns Hopkins University	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Johns Hopkins University
• University of California, San Francisco
• National Multiple Sclerosis Society

Investigators

• Principal Investigator: Ellen M Mowry, MD, MCR, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01667796
• Other Study ID Numbers: NA_00049428; FG-1507-05231
• First Posted: Aug 17, 2012
• Last Update Posted: Mar 5, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Johns Hopkins University: Multiple sclerosis; Healthy controls; Pharmacokinetics; Vitamin D
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Vitamin D; Cholecalciferol

Study Results

Participant Flow

Arm/Group Title	Multiple Sclerosis (MS) Subjects	Healthy Controls
Arm/Group Description	MS patients	Healthy control subjects
Period Title: Overall Study
STARTED	27	30
COMPLETED	24	29
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	MS Subjects	Healthy Controls	Total
Arm/Group Description	Female subjects with MS	Female subjects without MS	Total of all reporting groups
Overall Participants	27	30	57
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.2 (9.2)	37.9 (12.1)	38.9 (10.8)
Sex: Female, Male (Count of Participants)
Female	27 100%	30 100%	57 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	27 100%	30 100%	57 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	27 100%	30 100%	57 100%

Outcome Measures

1. Primary Outcome

Title	Change in Mean Serum Level of 25-hydroxyvitamin D
Description	Generalized estimating equations (GEE) with an autoregressive with lag one correlation matrix were used to compare the serially-measured serum 25(OH)D levels between MS patients and Healthy Controls (HCs) to take into account repeated measures and within-subject correlations.
Time Frame	Baseline to 90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MS Subjects	Healthy Controls
Arm/Group Description	Female subjects with MS	Female subjects without MS
Measure Participants	24	29
Mean (Standard Deviation) [nmol/L]	65.9 (5.9)	82.4 (5.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MS Subjects, Healthy Controls
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	univariate generalized estimating equati
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MS Subjects, Healthy Controls
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	Adjusted for adherence, body mass index, and oral contraceptive use
	Method	Generalized estimating equation
	Comments

2. Secondary Outcome

Title	Change in Percentages of T Cell Subsets (IFNγ+ and IL-17+)
Description	Analyzed the mean percentage change in IFNγ+ and IL-17+ cluster of differentiation 4 (CD4) + cells (post- versus pre- supplementation). This represents a change between two time points (90 days versus baseline).
Time Frame	Baseline, 90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MS Subjects	Healthy Controls
Arm/Group Description	MS patients	Healthy control subjects
Measure Participants	11	14
mean percentage change in IFNγ+ CD4+ cells	-5.2 (4.2)	-13.2 (3.2)
mean percentage change in IL-17+ CD4+ cells	0.21 (0.77)	-0.17 (1.14)

3. Secondary Outcome

Title	Gene Expression Microarray
Description	We had initially planned to do whole blood gene expression. The experience gained by the laboratory that was to perform this since the original trial was planned was that this measure is too noisy and would not yield meaningful results. Thus, this analysis will no longer be conducted.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

We had initially planned to do whole blood gene expression. The experience gained by the laboratory that was to perform this since the original trial was planned was that this measure is too noisy and would not yield meaningful results. Thus, this analysis will no longer be conducted.

Arm/Group Title	Gene Expression: MS vs HC
Arm/Group Description	Gene expression analyses have been cancelled as a secondary outcome as laboratory techniques developed since the original study was started indicated that whole blood gene expression is unlikely to be informative.
Measure Participants	0

4. Secondary Outcome

Title	Change in Cytokine Levels
Description	The original plan had been to measure the change in basic serum cytokine levels (e.g. IL-17, interferon gamma; IL-10; pg/microliter). However, due to emerging data suggesting low utility of these measures, this plan was abandoned.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Cytokine levels data were not analyzed and are no longer planned to be measured as outcomes.

Arm/Group Title	Multiple Sclerosis (MS) Subjects	Healthy Controls
Arm/Group Description	MS patients	Healthy control subjects
Measure Participants	0	0

5. Secondary Outcome

Title	Change in Percentage of B Cells
Description	The change in percentage (day 90-baseline) was originally planned for study. Due to the limited number of patients with samples this plan was abandoned.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

B Cell data were not analyzed and are no longer planned to be measured as outcomes.

Arm/Group Title	Multiple Sclerosis (MS) Subjects	Healthy Controls
Arm/Group Description	MS patients	Healthy control subjects
Measure Participants	0	0

Adverse Events

Arm/Group Title	MS Subjects		Healthy Controls
Arm/Group Description	MS patients		Healthy control subjects
All Cause Mortality
	MS Subjects		Healthy Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	MS Subjects		Healthy Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	MS Subjects		Healthy Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		1/30 (3.3%)
Cardiac disorders
Palpitations	0/27 (0%)		1/30 (3.3%)

Limitations/Caveats

The generalizability of the findings of this study (beyond female Caucasians) has to be further tested. It is possible that there were unmeasured confounders influencing results.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.