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

Diabetes Clinical Trial

— THINK-D  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02416193
• Other study ID #: 206988
• Secondary ID: 206988031815
• Status: Terminated
• Phase: Phase 2
• Start date: September 23, 2015
• Est. completion date: July 12, 2018

Study information

• Verified date: September 2020
• Source: Loyola University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 56
• Est. completion date: July 12, 2018
• Est. primary completion date: July 12, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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%

Related Conditions & MeSH terms

• Diabetes
• Diabetes Mellitus
• Executive Dysfunction

Intervention

Drug:
• Cholecalciferol
Participants will take randomly assigned high dose cholecalciferol once weekly for three months
• Cholecalciferol
Participants will take randomly assigned active comparator cholecalciferol once weekly for three months

Locations

Country	Name	City	State
United States	Loyola University Medical Center	Maywood	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
Loyola University	University of Chicago

Country where clinical trial is conducted

United States, 

References & Publications (40)

Alves MR, Yamamoto T, Arias-Carrión O, Rocha NB, Nardi AE, Machado S, Silva AC. Executive function impairments in patients with depression. CNS Neurol Disord Drug Targets. 2014;13(6):1026-40. Review. — View Citation

Annweiler C, Montero-Odasso M, Llewellyn DJ, Richard-Devantoy S, Duque G, Beauchet O. Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis. 2013;37(1):147-71. doi: 10.3233/JAD-130452. Review. — View Citation

Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch HM, Cheung R, Gagne D, D'Souza C, Ursell M, O'Connor P. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010 Jun 8;74(23):1852-9. doi: 10.1212/WNL.0b013e3181e1cec2. Epub 2010 Apr 28. Erratum in: Neurology. 2010 Aug 3;75(5):480. Neurology. 2010 Sep 14;75(11):1029. Dosage error in article text. — View Citation

Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. — View Citation

Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav. 1983 Dec;24(4):385-96. — View Citation

Cummings SR, Block G, McHenry K, Baron RB. Evaluation of two food frequency methods of measuring dietary calcium intake. Am J Epidemiol. 1987 Nov;126(5):796-802. — View Citation

Davidson MB, Duran P, Lee ML, Friedman TC. High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. Diabetes Care. 2013 Feb;36(2):260-6. doi: 10.2337/dc12-1204. Epub 2012 Oct 1. — View Citation

Drechsler C, Schmiedeke B, Niemann M, Schmiedeke D, Krämer J, Turkin I, Blouin K, Emmert A, Pilz S, Obermayer-Pietsch B, Weidemann F, Breunig F, Wanner C. Potential role of vitamin D deficiency on Fabry cardiomyopathy. J Inherit Metab Dis. 2014 Mar;37(2):289-95. doi: 10.1007/s10545-013-9653-8. Epub 2013 Oct 19. — View Citation

Endicott J, Nee J. Endicott Work Productivity Scale (EWPS): a new measure to assess treatment effects. Psychopharmacol Bull. 1997;33(1):13-6. — View Citation

Etgen T, Sander D, Bickel H, Sander K, Förstl H. Vitamin D deficiency, cognitive impairment and dementia: a systematic review and meta-analysis. Dement Geriatr Cogn Disord. 2012;33(5):297-305. doi: 10.1159/000339702. Epub 2012 Jul 2. Review. — View Citation

Gameroff MJ, Wickramaratne P, Weissman MM. Testing the Short and Screener versions of the Social Adjustment Scale-Self-report (SAS-SR). Int J Methods Psychiatr Res. 2012 Mar;21(1):52-65. doi: 10.1002/mpr.358. Epub 2011 Dec 5. — View Citation

Geijselaers SLC, Sep SJS, Stehouwer CDA, Biessels GJ. Glucose regulation, cognition, and brain MRI in type 2 diabetes: a systematic review. Lancet Diabetes Endocrinol. 2015 Jan;3(1):75-89. doi: 10.1016/S2213-8587(14)70148-2. Epub 2014 Aug 24. Review. Erratum in: Lancet Diabetes Endocrinol. 2015 Jan;3(1):e1. — View Citation

Glanz K, Yaroch AL, Dancel M, Saraiya M, Crane LA, Buller DB, Manne S, O'Riordan DL, Heckman CJ, Hay J, Robinson JK. Measures of sun exposure and sun protection practices for behavioral and epidemiologic research. Arch Dermatol. 2008 Feb;144(2):217-22. doi: 10.1001/archdermatol.2007.46. — View Citation

Grober E, Hall CB, Hahn SR, Lipton RB. Memory Impairment and Executive Dysfunction are Associated with Inadequately Controlled Diabetes in Older Adults. J Prim Care Community Health. 2011 Oct 1;2(4):229-33. doi: 10.1177/2150131911409945. Epub 2011 Jun 1. — View Citation

Gulseth HL, Gjelstad IM, Tierney AC, Lovegrove JA, Defoort C, Blaak EE, Lopez-Miranda J, Kiec-Wilk B, Risérus U, Roche HM, Drevon CA, Birkeland KI. Serum vitamin D concentration does not predict insulin action or secretion in European subjects with the metabolic syndrome. Diabetes Care. 2010 Apr;33(4):923-5. doi: 10.2337/dc09-1692. Epub 2010 Jan 12. Erratum in: Diabetes Care. 2010 Dec;33(12):2725. Ris, Ulférus [corrected to Risérus, Ulf]. — View Citation

Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30. doi: 10.1210/jc.2011-0385. Epub 2011 Jun 6. Erratum in: J Clin Endocrinol Metab. 2011 Dec;96(12):3908. — View Citation

Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006 Mar;81(3):353-73. Review. — View Citation

Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81. Review. — View Citation

Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008 Dec;264(6):599-609. doi: 10.1111/j.1365-2796.2008.02008.x. Epub 2008 Sep 10. — View Citation

Koutkia P, Lu Z, Chen TC, Holick MF. Treatment of vitamin D deficiency due to Crohn's disease with tanning bed ultraviolet B radiation. Gastroenterology. 2001 Dec;121(6):1485-8. — View Citation

Lee JH, Choi Y, Jun C, Hong YS, Cho HB, Kim JE, Lyoo IK. Neurocognitive changes and their neural correlates in patients with type 2 diabetes mellitus. Endocrinol Metab (Seoul). 2014 Jun;29(2):112-21. doi: 10.3803/EnM.2014.29.2.112. Review. — View Citation

Lips P. Which circulating level of 25-hydroxyvitamin D is appropriate? J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):611-4. Review. — View Citation

Littlejohns TJ, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PH, Fried L, Kestenbaum BR, Kuller LH, Langa KM, Lopez OL, Kos K, Soni M, Llewellyn DJ. Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 2014 Sep 2;83(10):920-8. doi: 10.1212/WNL.0000000000000755. Epub 2014 Aug 6. — View Citation

McCann JC, Ames BN. Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction? FASEB J. 2008 Apr;22(4):982-1001. Epub 2007 Dec 4. Review. — View Citation

Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic ß cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr. 2011 Aug;94(2):486-94. doi: 10.3945/ajcn.111.011684. Epub 2011 Jun 29. — View Citation

Munshi MN, Hayes M, Iwata I, Lee Y, Weinger K. Which aspects of executive dysfunction influence ability to manage diabetes in older adults? Diabet Med. 2012 Sep;29(9):1171-7. doi: 10.1111/j.1464-5491.2012.03606.x. — View Citation

Nazarian S, St Peter JV, Boston RC, Jones SA, Mariash CN. Vitamin D3 supplementation improves insulin sensitivity in subjects with impaired fasting glucose. Transl Res. 2011 Nov;158(5):276-81. doi: 10.1016/j.trsl.2011.05.002. Epub 2011 Jun 7. — View Citation

Penckofer S, Kouba J, Byrn M, Estwing Ferrans C. Vitamin D and depression: where is all the sunshine? Issues Ment Health Nurs. 2010 Jun;31(6):385-93. doi: 10.3109/01612840903437657. — View Citation

Penckofer S, Kouba J, Wallis DE, Emanuele MA. Vitamin D and diabetes: let the sunshine in. Diabetes Educ. 2008 Nov-Dec;34(6):939-40, 942, 944 passim. doi: 10.1177/0145721708326764. Review. — View Citation

Recker RR, Gallagher R, MacCosbe PE. Effect of dosing frequency on bisphosphonate medication adherence in a large longitudinal cohort of women. Mayo Clin Proc. 2005 Jul;80(7):856-61. — View Citation

Retracted: Executive dysfunction in elderly diabetic patients. Geriatr Gerontol Int. 2015 Aug;15(8):1106. doi: 10.1111/ggi.12288. Epub 2014 Apr 21. — View Citation

Ruff RM, Light RH, Parker SB, Levin HS. Benton Controlled Oral Word Association Test: reliability and updated norms. Arch Clin Neuropsychol. 1996;11(4):329-38. — View Citation

Schlögl M, Holick MF. Vitamin D and neurocognitive function. Clin Interv Aging. 2014 Apr 2;9:559-68. doi: 10.2147/CIA.S51785. eCollection 2014. Review. — View Citation

Smith MA, Else JE, Paul L, Foster JK, Walker M, Wesnes KA, Riby LM. Functional Living in Older Adults With Type 2 Diabetes: Executive Functioning, Dual Task Performance, and the Impact on Postural Stability and Motor Control. J Aging Health. 2014 Aug;26(5):841-859. Epub 2014 Jun 4. — View Citation

Tuligenga RH, Dugravot A, Tabák AG, Elbaz A, Brunner EJ, Kivimäki M, Singh-Manoux A. Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study. Lancet Diabetes Endocrinol. 2014 Mar;2(3):228-35. doi: 10.1016/S2213-8587(13)70192-X. Epub 2013 Dec 19. — View Citation

Wallis DE, Penckofer S, Sizemore GW. The "sunshine deficit" and cardiovascular disease. Circulation. 2008 Sep 30;118(14):1476-85. doi: 10.1161/CIRCULATIONAHA.107.713339. Review. Erratum in: Circulation. 2009 Jun 2;119(21):e550. — View Citation

Welch G, Weinger K, Anderson B, Polonsky WH. Responsiveness of the Problem Areas In Diabetes (PAID) questionnaire. Diabet Med. 2003 Jan;20(1):69-72. Review. — View Citation

Wennberg AM, Gottesman RF, Kaufmann CN, Albert MS, Chen-Edinboro LP, Rebok GW, Kasper JD, Spira AP. Diabetes and cognitive outcomes in a nationally representative sample: the National Health and Aging Trends Study. Int Psychogeriatr. 2014 Oct;26(10):1729-35. doi: 10.1017/S1041610214001380. Epub 2014 Jul 30. — View Citation

Winkler A, Dlugaj M, Weimar C, Jöckel KH, Erbel R, Dragano N, Moebus S. Association of diabetes mellitus and mild cognitive impairment in middle-aged men and women. J Alzheimers Dis. 2014;42(4):1269-77. doi: 10.3233/JAD-140696. — View Citation

Zahodne LB, Nowinski CJ, Gershon RC, Manly JJ. Depressive symptoms are more strongly related to executive functioning and episodic memory among African American compared with non-Hispanic White older adults. Arch Clin Neuropsychol. 2014 Nov;29(7):663-9. doi: 10.1093/arclin/acu045. Epub 2014 Oct 3. — View Citation

* Note: There are 40 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
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.	13 Weeks
Primary	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
Primary	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
Primary	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	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
Secondary	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