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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02416193

Acronym

THINK-D

Enrollment

Registered

2015-04-14

Start date

2015-09-23

Completion date

2018-07-12

Last updated

2020-10-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes, Executive Dysfunction

Keywords

Diabetes, Cognition, Functioning

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.

Interventions

DRUGCholecalciferol

Participants will take randomly assigned high dose cholecalciferol once weekly for three months

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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%

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.
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.

Secondary

Measure	Time frame	Description
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.
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.

Countries

United States

Participant flow

Recruitment details

Recruitment for this study took place at Loyola University Medical Center (Maywood, IL) between September 2015 and June 2018

Pre-assignment details

Fifty-six participants consented to participate in the study. Among these individuals, 26 (46.43%) were not randomized and were excluded from continuing their participation in the study because the medical monitor determined they did not meet study inclusion criteria.

Participants by arm

Arm	Count
Low Dose 5,000 IU cholecalciferol once weekly for three months	15
High Dose 50,000 IU cholecalciferol once weekly for three months	15
Total	30

Baseline characteristics

Characteristic	Low Dose	Total	High Dose
Activity level Insufficiently active	5 Participants	11 Participants	6 Participants
Activity level Moderately active	3 Participants	6 Participants	3 Participants
Activity level Sufficiently active	7 Participants	13 Participants	6 Participants
Age, Continuous	55.62 years STANDARD_DEVIATION 10.14	55.71 years STANDARD_DEVIATION 9.74	55.80 years STANDARD_DEVIATION 9.68
Body mass index	40.44 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 9.48	37.32 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 8.11	34.20 kilograms per meter squared (kg/m^2) STANDARD_DEVIATION 5.05
Calcium	9.40 milligrams per deciliter (mg/dL)	9.50 milligrams per deciliter (mg/dL)	9.60 milligrams per deciliter (mg/dL)
CES-D Score	7.13 units on a scale STANDARD_DEVIATION 3.46	8.43 units on a scale STANDARD_DEVIATION 4.32	9.73 units on a scale STANDARD_DEVIATION 4.8
Creatinine	0.74 milligrams per deciliter (mg/dL)	0.79 milligrams per deciliter (mg/dL)	0.83 milligrams per deciliter (mg/dL)
Diastolic blood pressure	73.47 Millimeters of mercury (mmHg) STANDARD_DEVIATION 10.99	73.20 Millimeters of mercury (mmHg) STANDARD_DEVIATION 10.7	72.93 Millimeters of mercury (mmHg) STANDARD_DEVIATION 10.79
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	6 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants	23 Participants	13 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants
Glucose	120 Millimoles per liter (mmol/L)	134 Millimoles per liter (mmol/L)	142 Millimoles per liter (mmol/L)
HbA1c	7.10 mmol/mol	7.15 mmol/mol	7.20 mmol/mol
Heart rate	73.27 Beats per minute (BPM) STANDARD_DEVIATION 12.67	74.63 Beats per minute (BPM) STANDARD_DEVIATION 12.62	76.00 Beats per minute (BPM) STANDARD_DEVIATION 12.86
Martial status Currently married	10 Participants	14 Participants	4 Participants
Martial status Divorced	2 Participants	7 Participants	5 Participants
Martial status Never married	1 Participants	6 Participants	5 Participants
Martial status Separated	0 Participants	1 Participants	1 Participants
Martial status Widowed	2 Participants	2 Participants	0 Participants
Patient Health Questionnaire-9	2 units on a scale	3 units on a scale	4 units on a scale
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	8 Participants	17 Participants	9 Participants
Race (NIH/OMB) More than one race	1 Participants	2 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	5 Participants	9 Participants	4 Participants
Region of Enrollment United States	15 participants	30 participants	15 participants
Season of first dose of the study drug Fall	5 Participants	10 Participants	5 Participants
Season of first dose of the study drug Spring	5 Participants	6 Participants	1 Participants
Season of first dose of the study drug Summer	2 Participants	5 Participants	3 Participants
Season of first dose of the study drug Winter	3 Participants	9 Participants	6 Participants
Serum vitamin D3 level	21 Nanograms per milliliter (ng/mL)	22 Nanograms per milliliter (ng/mL)	24 Nanograms per milliliter (ng/mL)
Sex: Female, Male Female	14 Participants	25 Participants	11 Participants
Sex: Female, Male Male	1 Participants	5 Participants	4 Participants
Systolic blood pressure	134.73 Millimeters of mercury (mmHg) STANDARD_DEVIATION 16.33	132.93 Millimeters of mercury (mmHg) STANDARD_DEVIATION 16.45	131.13 Millimeters of mercury (mmHg) STANDARD_DEVIATION 16.95
Total vitamin D level	21 Nanograms per milliliter (ng/mL)	24 Nanograms per milliliter (ng/mL)	25 Nanograms per milliliter (ng/mL)
WRAT-IV Reading Score	-1.00 units on a scale	-0.97 units on a scale	-0.93 units on a scale
Years of education	14 years	14 years	14 years

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 15	0 / 15
other Total, other adverse events	12 / 15	9 / 15
serious Total, serious adverse events	0 / 15	1 / 15

Outcome results

Primary

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.

Time frame: 13 Weeks