Can Vitamin D3 Improve Cognitive Function in Individuals With Type 2 Diabetes? (THINK-D)

Study Overview
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Brief Summary
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Diabetes increases the risk of cognitive dysfunction. The incidence of dementia is 1.5 to 2.5 times higher in persons with diabetes than the general population. There is evidence that cognitive decline significantly impacts the ability to self-manage diabetes. Strategies to prevent cognitive decline in persons with diabetes has not been well studied. A recent study reported that in persons who had vitamin D deficiency, the risk for all-cause dementia and Alzheimer's was doubled. Vitamin D receptors are located in the brain and deficiency of vitamin D has been reported to negatively affect the development of brain. Therefore, providing vitamin D supplementation to improve cognitive function is worthy of study. The investigators propose a small, randomized controlled trial to determine the effects of vitamin D3 supplementation in persons with type 2 diabetes who have symptoms of cognitive impairment. Persons will be randomized to receive either weekly vitamin D3 supplementation (50,000 IUs) or a matching comparator (5000 IUs) for a period of three months. The study aims are to determine (1) the effect of vitamin D3 supplementation on cognitive function and (2) the effect of vitamin D3 supplementation on diabetes self-management. A sample of persons with type 2 diabetes (n=62), who have a subjective complaint of a cognitive dysfunction or scoring at least one standard deviation below normal on a cognitive functioning screening test, have vitamin D levels less 30 ng/ml, are not depressed (as this impacts cognitive function), and do not have severe diabetes complication will be recruited. Participants will be phone screened and complete two baseline visits prior to randomization. They will then have phone call and follow-up visits to assess (1) cognitive function using standardized tests to assess for executive function (2) serum measurements (HBA1c, fasting glucose, vitamin D levels, and cardiometabolic profile) and (3) surveys to assess cognitive function as well as self-management behaviors.

Detailed Description
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Study Aims Diabetes increases the risk of cognitive dysfunction. The incidence of dementia is 1.5 to 2.5 times higher in persons with diabetes than the general population (1). There is evidence that cognitive decline significantly impacts the ability to self-manage diabetes (2). Strategies to prevent cognitive decline in persons with diabetes has not been well studied. A recent study reported that in persons who had vitamin D deficiency, the risk for all-cause dementia and Alzheimer's was doubled (3). Vitamin D receptors are located in the brain, and deficiency of vitamin D has been reported to negatively affect the development of brain and impact both growth factor signaling and neural activity (4, 5). Therefore, providing vitamin D supplementation to improve cognitive function in persons with diabetes who are at great risk for this comorbid condition is important. The investigators propose a small, randomized controlled trial to determine the effects of vitamin D3 supplementation in persons with type 2 diabetes who have symptoms of cognitive impairment. Persons will be randomized to receive either weekly vitamin D3 supplementation (50,000 IUs) or a matching comparator (5000 IUs) for a period of three months. Primary Aim: To determine the effect of vitamin D3 supplementation on cognitive function for persons with type 2 diabetes. Primary Hypothesis: Persons receiving weekly vitamin D3 supplementation (50,000 IUs) will have improved cognitive function compared to those receiving the comparator (5000 IUs) at three months. Secondary Aim: To determine the effect of vitamin D3 supplementation on diabetes self-management. Secondary Hypothesis: Persons receiving weekly vitamin D3 supplementation (50,000 IUs) will have improved self-management compared to those receiving the comparator (5000 IUs) at three months. The importance of this study is several fold. Vitamin D supplementation is a low cost intervention (6), it has minimal side effects (7), and it could have high impact for persons with type 2 diabetes who suffer from cognitive impairment which can significantly affect their diabetes self-management.

Official Title
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Can Vitamin D3 Improve Cognitive Function in Individuals With Type 2 Diabetes? (THINK-D)

Conditions
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Diabetes, Executive Dysfunction

Intervention / Treatment
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* Drug: Cholecalciferol
* Drug: Cholecalciferol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women and men aged 18 to 75 years Have type 2 diabetes Having a subjective complaint of a cognitive dysfunction or scoring at least one standard deviation below normal on a cognitive functioning screening test Vitamin D level as measured by 25-hydroxyvitamin D (25-OH D) < 32 ng/mL Under the care of a healthcare provider Systolic blood pressure ≤160 and diastolic blood pressure ≤100 Exclusion Criteria: Persons with malabsorption problems (e.g., crohn's disease) Hypercalcemia Supplementation other than a daily multivitamin Severe complications of diabetes (i.e., amputation, blindness, and dialysis) Concomitant use of steroids GFR < 60 Creatinine > 1.2 Significant depressive symptoms Having a history of bipolar depression, psychotic disorders, loss of consciousness greater than 5 minutes, or a current alcohol or substance use disorder Other serious medical conditions deemed significant by the PI or medical monitor Concomitant use of cholinesterase inhibitors Concomitant use of anxiolytics, kava kava, St. John's Wort, or Ginkgo Biloba Pregnancy HbA1c >13%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose<br>50,000 IU cholecalciferol once weekly for three months | Drug: Cholecalciferol<br>* Participants will take randomly assigned high dose cholecalciferol once weekly for three months<br>* Other names: Vitamin D3;|
| Active Comparator: Low Dose<br>5,000 IU cholecalciferol once weekly for three months | Drug: Cholecalciferol<br>* Participants will take randomly assigned active comparator cholecalciferol once weekly for three months<br>* Other names: Vitamin D3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Letter-Number Sequencing | The the Letter-Number Sequencing Test (from the Wechsler Adult Intelligence Scale-III assessment) is an assessment of working memory. Scores on the assessment are standardized as scaled scores with a mean of 10 and standard deviation of 3 (μ = 10, SD = 3) using age adjusted normative data provided by Pearson assessments (https://www.pearsonassessments.com/). A scaled score indicates the number of standard deviations away from the mean. A scaled score of 10 is equal to the mean. Scaled scores below 10 indicate performance is lower than average, and scaled scores higher than 10 indicate performance is higher than average. Higher scaled scores indicate better performance. | 13 weeks | 
| Controlled Oral Word Association Test | The Controlled Oral Word Association Test is a measure of verbal fluency. Scores are standardized as z-scores (μ = 0, SD = 1) using age adjusted normative data provided by Tombaugh and Kozak (1996). A z-score indicates the number of standard deviations away from the mean. A z-score of 0 is equal to the mean. Negative z-scores indicate performance is lower than average, and positive z-scores indicate performance is higher than average. Positive z-scores indicate better performance. | 13 Weeks | 
| Stroop Interference Test | The Stroop Interference Test is a measure of executive functioning. Scores are standardized as z-scores (μ = 0, SD = 1) using age adjusted normative data provided by PAR Incorporated (https://www.parinc.com/). A z-score indicates the number of standard deviations away from the mean. A z-score of 0 is equal to the mean. Negative z-scores indicate performance is lower than average, and positive z-scores indicate performance is higher than average. Positive z-scores indicate better performance. | 13 Weeks | 
| Symbol-Digit Modality Test | The Symbol-Digit Modality Test is a measure of executive functioning. Scores are standardized as z-scores (μ = 0, SD = 1) using age adjusted normative data provided by WPS Publishers (https://www.wpspublish.com/). A z-score indicates the number of standard deviations away from the mean. A z-score of 0 is equal to the mean. Negative z-scores indicate performance is lower than average, and positive z-scores indicate performance is higher than average. Positive z-scores indicate better performance. | 13 Weeks | 
| Trail Making Test Part B | The Trail Making Test Part B is a measure of executive functioning. Scores are standardized as z-scores (μ = 0, SD = 1) using age adjusted normative data provided by WPS Publishers (https://www.wpspublish.com/). A z-score indicates the number of standard deviations away from the mean. A z-score of 0 is equal to the mean. Negative z-scores indicate performance is lower than average, and positive z-scores indicate performance is higher than average. Positive z-scores indicate better performance. | 13 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hopkins Verbal Learning Total Recall Test | The Hopkins Verbal Learning Total Recall Test is an assessment of memory. Scores are standardized as T-scores (μ = 50, SD = 10) using age adjusted normative data provided by PAR Incorporated (https://www.parinc.com/). A T-score indicates the number of standard deviations away from the mean. A T-score of 50 is equal to the mean. T-scores below 50 indicate performance is lower than average, and T-scores above 50 indicate performance is higher than average. Higher T-scores indicate better performance. | 13 weeks | 
| Semantic Fluency Test | The Semantic Fluency Test is a measure of verbal fluency. Scores are standardized as z-scores (μ = 0, SD = 1) using age adjusted normative data provided by Tombaugh and Kozak (1996). A z-score indicates the number of standard deviations away from the mean. A z-score of 0 is equal to the mean. Negative z-scores indicate performance is lower than average, and positive z-scores indicate performance is higher than average. Positive z-scores indicate better performance. | 13 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Cognition, Functioning