Longitudinal Effect of Vitamin D3 Replacement on Cognitive Performance and MRI Markers in Multiple Sclerosis Patients

Longitudinal Effect of Vitamin D3 Replacement on Cognitive Performance and MRI Markers in Multiple Sclerosis Patients: A Single-Blind Randomized Clinical Trial

This is a longitudinal single blind randomized trial to test the effects of high compared to low dose vitamin D3 supplementation on cognitive performance at 6 and 12 months, and MRI measures of 12 months duration. A cognitive assessment battery will be administered at baseline, 6 and 12 months. Related clinical data and information on depression and anxiety, lifestyle, and food sources of vitamin D and sun exposure among other variables will also be collected.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis; Clinically Isolated Syndrome; Multiple Sclerosis, Relapsing-Remitting; Clinically Isolated Syndrome, CNS Demyelinating; Vitamin D3 Deficiency
• Intervention / Treatment: Dietary supplement: Vitamin D3

Detailed Description

Background: Multiple Sclerosis is strongly associated with low serum 25 hydroxy-vitamin-D (25(OH)D) and impaired cognitive performance. In our previous research, participants with low serum 25OHD levels showed significant improvements in visuo-spatial memory delayed recall after 3 months of vitamin D3 supplementation. In addition, serum 25(OH)D was significantly associated with this memory function at baseline and at 3 months. Therefore, the aim of this proposed study is 1) to evaluate the long-term effects 6 and 12 months of high (50,000 IU weekly then 10,000 IU weekly) compared to low dose (800 IU daily) vitamin D3 replacement on cognitive function in MS, and 2) to correlate it with the MRI brain measurements of the hippocampus and the frontal cortex volumes, as well as brain parenchymal fraction, and cerebellum. The investigators will then explore these MRI measures in MS patients with deficient 25(OH)D levels at baseline and at 12 months, and correlate it with their cognitive performance.

Methods: This is a longitudinal single blind randomized trial to test the effects of high compared to low dose vitamin D3 supplementation on cognitive performance at 6 and 12 months, and MRI measures of 12 months duration. A cognitive assessment battery, comprised of the Montreal Cognitive Assessment (only at baseline), Stroop, Symbol Digit Modalities Test, Brief Visual Memory Test, and Verbal Memory Test in Arabic, will be administered at baseline, 6 and 12 months. Related clinical data and information on depression and anxiety, lifestyle, and food sources of vitamin D and sun exposure among other variables will also be collected.

Expected results: MS patients with serum 25(OH)D deficiency who receive high dose vitamin D3 supplementation will demonstrate decreased cognitive impairment at 6 and 12 months post supplementation when compared to those who received low vitamin D3 dose and to their pre-supplementation status. The MRI findings are expected to be associated with cognitive performance at baseline, and serum 25(OH)D levels at baseline, and 12 months.

• Study Type: Interventional
• Enrollment (Anticipated): 162
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hala Darwish, PhD, RN; Phone Number: 7427 +961-1-350000; Email: hd30@aub.edu.lb

Study Locations

• Lebanon
  • Beirut, Lebanon, 1107 2020
    • Recruiting
    • Nehme & Therese Tohme Multiple Sclerosis Center
    • Contact: Samia Khoury, MD; Phone Number: 7420 +961-1-350000; Email: sk88@aub.edu.lb
    • Principal Investigator: Hala Darwish, PhD, RN
    • Principal Investigator: Samia Khoury, MD
    • Principal Investigator: Hani Tamim, PhD
    • Sub-Investigator: Nabil Ayoubi, MD
    • Sub-Investigator: Salem Hannoun, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent form
• Males/ Females
• Age ≥ 18 years old
• Have a definite diagnosis of RRMS as per the revised McDonald 2010 or CIS.
• Untreated or on any MS therapy
• Showed no clinical evidence of relapses during the past month and disease duration not greater than 10 years.
• Subjects who have a serum vitamin D level below 25 ng/ml

Exclusion Criteria:

• All subjects using drugs associated with hypercalcemia.
• Pregnant and with history of primary hyper PTH.
• Subjects with hypercalcemia, renal dysfunction, malignancy, or granulomatous disease, dementia, traumatic brain injury, diagnosis of epilepsy or history of seizure, psychiatric disease other than anxiety and depression, or are found to be suicidal on screening, or taking psychoactive medications other than antidepressants
• Subjects who have a serum vitamin D level above 25 ng/ml
• Subjects who have not done an MRI scan up to 3 months before or after the baseline visit.
• Subjects who have a history of kidney stones
• Subjects with malabsorption
• Individuals with history of alcohol abuse/dependence and/or substance use/abuse/dependence will also be excluded from the study. Men who consume more than 15 drinks per week and women who consume more than eight drinks per week will be considered excessive alcohol consumers and will be excluded from the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: low dose vitamin D3 supplementation; Patients in this group will take 800 IU daily dose of vitamin D supplementation. They will be kept on 800 IU for 6 months. If they still had low vitamin D at 3 months, they will be asked about their adherence to the supplement, the investigators will remind them to take it as prescribed, and the investigators will keep the 800 IU vitamin D supplement dose for another 3 months. If they were still deficient at 6 months, the investigators will switch them to 10,000 IU weekly dose.	Dietary supplement: Vitamin D3; At baseline, patients with deficient 25(OH)D levels will be randomly assigned 1:1 to receive either the high dose or standard dose vitamin D supplementation.
Experimental: high dose vitamin D3 supplementation; Patients in this group will take 50,000 IU weekly dose of vitamin D supplementation. Patients who will reach normal serum vitamin D level, between 40-80 ng/ml, at 3 or 6 months will be asked to decrease their Vitamin D3 supplementation as follows: Those who will reach levels between 40-60ng/ml will be switched to 10,000 IU three times per week, and those who reach levels between 60-80 ng/ml will be switched to 10,000 IU once weekly. If they did not have any improvement in their levels of vitamin D at 3 or 6 months, they will be asked about their adherence to the supplement and the investigators will remind them to take it as prescribed and the investigators will keep them at the 50,000 IU weekly dose.	Dietary supplement: Vitamin D3; At baseline, patients with deficient 25(OH)D levels will be randomly assigned 1:1 to receive either the high dose or standard dose vitamin D supplementation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline Brief Visuospatial Memory Test-Revised (BVMT-R) scores at 6 months	It is a visuospatial memory test that is comprised of three memory trials (10 seconds each) followed by delayed recall trial after 25 minutes. It has been widely used as a quick measure of memory at bedside and in MS patients. The minimum score on each trial is 0 and the maximum score on each trial is 12. Higher values represent a better outcome.	6 months
Change from Baseline Arabic Verbal Memory Test (VMAT) scores at 6 months	It is a verbal memory test. It consists of 45 words that are distributed among 3 lists (List A, List B, and a Recognition List). Lists A and B are each composed of 15 words belonging to 3 semantic categories: vegetables, animals, and stationary. The recognition list is composed 45 words that include homonyms, shared or related words and unrelated words with respect to the previous two lists. The VMAT is administered as follows: List A Immediate Free Recall (5 trials) - List B Immediate Free Recall Trial - List A Short Delay Free Recall Trial - List A Short Delay Cued Recall Trial - List A Long Delay Free Recall Trial - List A Long Delay Cued Recall Trial. After 25 minutes of the last trial, List A Delayed Recognition Trial is administered. For each trial, the minimum total score is 0 and the maximum total score is 15. Higher scores represent a better outcome. For each trial except the recognition trial, repeated and intrusive words are counted separately.	6 months
Change from Baseline Symbol Digit Modalities Test (SDMT) scores at 6 months	It is a known and widely used speed of processing test. Oral SDMT will be administered; it does not require translation and has been used in Lebanon before. It consists of one trial. The minimum total score is 0 and the maximum total score is 110. Higher scores represent a better outcome.	6 months
Change from Baseline Stroop test scores at 6 months	It is a highly established test of attention. Subject is given a list of colors in black ink to read (Stroop 1), then a list of colors in their corresponding ink color (Stroop 2), and then finally a list of colors with incongruent ink colors (Stroop 3), the participant is expected to read the word without being affected by interfering mismatching color. The number of words read in a minute (minus the errors) is the dependent measure and interference will be calculated using the following equation: Interference = Stroop 3 - [(Stroop 1+Stroop 2)/2]. For each of the 3 lists, the minimum total score is 0 and the maximum total score is 100. Higher scores represent a better outcome. For the interference, the minimum score is -100 and the maximum score is 0. Higher scores represent a better outcome.	6 months
Change from Baseline Brief Visuospatial Memory Test-Revised (BVMT-R) scores at 12 months	It is a visuospatial memory test that is comprised of three memory trials (10 seconds each) followed by delayed recall trial after 25 minutes. It has been widely used as a quick measure of memory at bedside and in MS patients. The minimum score on each trial is 0 and the maximum score on each trial is 12. Higher values represent a better outcome.	12 months
Change from Baseline Arabic Verbal Memory Test (VMAT) scores at 12 months	It is a verbal memory test. It consists of 45 words that are distributed among 3 lists (List A, List B, and a Recognition List). Lists A and B are each composed of 15 words belonging to 3 semantic categories: vegetables, animals, and stationary. The recognition list is composed 45 words that include homonyms, shared or related words and unrelated words with respect to the previous two lists. The VMAT is administered as follows: List A Immediate Free Recall (5 trials) - List B Immediate Free Recall Trial - List A Short Delay Free Recall Trial - List A Short Delay Cued Recall Trial - List A Long Delay Free Recall Trial - List A Long Delay Cued Recall Trial. After 25 minutes of the last trial, List A Delayed Recognition Trial is administered. For each trial, the minimum total score is 0 and the maximum total score is 15. Higher scores represent a better outcome. For each trial except the recognition trial, repeated and intrusive words are counted separately.	12 months
Change from Baseline Symbol Digit Modalities Test (SDMT) scores at 12 months	It is a known and widely used speed of processing test. Oral SDMT will be administered; it does not require translation and has been used in Lebanon before. It consists of one trial. The minimum total score is 0 and the maximum total score is 110. Higher scores represent a better outcome.	12 months
Change from Baseline Stroop test scores at 12 months	It is a highly established test of attention. Subject is given a list of colors in black ink to read (Stroop 1), then a list of colors in their corresponding ink color (Stroop 2), and then finally a list of colors with incongruent ink colors (Stroop 3), the participant is expected to read the word without being affected by interfering mismatching color. The number of words read in a minute (minus the errors) is the dependent measure and interference will be calculated using the following equation: Interference = Stroop 3 - [(Stroop 1+Stroop 2)/2]. For each of the 3 lists, the minimum total score is 0 and the maximum total score is 100. Higher scores represent a better outcome. For the interference, the minimum score is -100 and the maximum score is 0. Higher scores represent a better outcome.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline Magnetic Resonance Imaging Brain Markers of the Hippocampus volume at 12 months	Changes in baseline MRI brain measurements of the hippocampus volume will be assessed at 12 months.	12 months
Change from Baseline Magnetic Resonance Imaging Brain Markers of the frontal cortex volume at 12 months	Changes in baseline MRI brain measurements of the frontal cortex volumes will be assessed 12 months.	12 months
Change from Baseline Magnetic Resonance Imaging Brain Markers of the brain parenchymal fraction at 12 months	Changes in baseline MRI brain measurements of the brain parenchymal fraction will be assessed at 12 months.	12 months
Change from Baseline Magnetic Resonance Imaging Brain Markers of the Cerebellum at 12 months	Changes in baseline MRI brain measurements of the cerebellum will be assessed at 12 months.	12 months

Collaborators and Investigators

• Sponsor: American University of Beirut Medical Center
• Investigators: Principal Investigator: Hala Darwish, PhD, RN, American University of Beirut Medical Center

Publications and helpful links

General Publications

• Darwish H, Haddad R, Osman S, Ghassan S, Yamout B, Tamim H, Khoury S. Effect of Vitamin D Replacement on Cognition in Multiple Sclerosis Patients. Sci Rep. 2017 Apr 4;7:45926. doi: 10.1038/srep45926.
• Balion C, Griffith LE, Strifler L, Henderson M, Patterson C, Heckman G, Llewellyn DJ, Raina P. Vitamin D, cognition, and dementia: a systematic review and meta-analysis. Neurology. 2012 Sep 25;79(13):1397-405. doi: 10.1212/WNL.0b013e31826c197f.
• Darwish H, Zeinoun P, Ghusn H, Khoury B, Tamim H, Khoury SJ. Serum 25-hydroxyvitamin D predicts cognitive performance in adults. Neuropsychiatr Dis Treat. 2015 Aug 25;11:2217-23. doi: 10.2147/NDT.S87014. eCollection 2015.
• van der Schaft J, Koek HL, Dijkstra E, Verhaar HJ, van der Schouw YT, Emmelot-Vonk MH. The association between vitamin D and cognition: a systematic review. Ageing Res Rev. 2013 Sep;12(4):1013-23. doi: 10.1016/j.arr.2013.05.004. Epub 2013 May 29.

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2018
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: July 13, 2018
• First Submitted That Met QC Criteria: July 25, 2018
• First Posted (Actual): August 1, 2018

Study Record Updates

• Last Update Posted (Actual): August 30, 2021
• Last Update Submitted That Met QC Criteria: August 27, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: cognitive performance; vitamin D3 replacement; Lebanon
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Disease; Multiple Sclerosis; Sclerosis; Syndrome; Multiple Sclerosis, Relapsing-Remitting; Demyelinating Diseases; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: BIO-2017-0395

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

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