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

Phase 2

Terminated

Conditions: Diabetes
Executive Dysfunction

Interventions: Drug: Cholecalciferol

Registration Number: NCT02416193

Lead Sponsor: Loyola University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 56

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%

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
High Dose	Cholecalciferol	50,000 IU cholecalciferol once weekly for three months
Low Dose	Cholecalciferol	5,000 IU cholecalciferol once weekly for three months

Primary Outcome Measures

Name	Time	Method
Letter-Number Sequencing	13 weeks	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.
Controlled Oral Word Association Test	13 Weeks	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.
Stroop Interference Test	13 Weeks	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.
Symbol-Digit Modality Test	13 Weeks	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.
Trail Making Test Part B	13 Weeks	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.

Secondary Outcome Measures

Name	Time	Method
Hopkins Verbal Learning Total Recall Test	13 weeks	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.
Semantic Fluency Test	13 Weeks	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.