Zeenat Ali, PGY3 Joseph Grisanti , MD June 7 th , 2012

1. University at Buffalo The state University of New York A Randomized Open Label Trial to Evaluate the Efficacy of Different Dosage Forms of Vitamin D in Patients with Vitamin D Deficiency, and the Effect of Food on Vitamin D Absorption. Zeenat Ali, PGY3 Joseph Grisanti, MD June 7th, 2012

2. Introduction • Low vitamin D levels have been implicated in a number of diseases. • Vitamin D deficiency causes rickets among children and a painful bone disease osteomalacia among adults. • It also precipitates and exacerbates osteoporosis among adults. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J ClinNutr; 2004; 80; 1678-1688.

3. Introductioncontd… • Vitamin D deficiency has been associated with • Cancers • Hypertension • Cardiovascular diseases Spina CS, Tangpricha V. Vitamin D and cancer. Anticancer Res. 2006; 26; 2515-2524 Pilz S, Vitamin D status and arterial hypertension. A systematic review. Nat Rev Cardiol. 2009; 6; 621-630 GiovannucciE. 25-hydroxyvitamin D and risk of myocardial infarction in men. A prospective study. Arch Intern Med; 2008; 168; 1174-1180.

4. Introductioncontd… • Vitamin D deficiency has also been linked with • Multiple sclerosis • Rheumatoid arthritis • Type 1 diabetes mellitus MungerKL. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006; 296; 2832-2838. Patel S. Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum. 2007; 56; 2143-2149. Mohr SB. The association between ultraviolet B irradiance, vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Daibetologia. 2008; 51; 1391-1398.

5. Introductioncontd… • It has been estimated that 1 billion people worldwide have vitamin D deficiency (25-hydroxy (OH) vitamin D< 20ng/ml) or insufficiency (25-OH vitamin D between 21-29 ng/ml). • Up to 57% of general medicine inpatients in the United States have been reported to have insufficient or deficient vitamin D levels. Holick MF. High prevalence of vitamin D inadequancy and implications for health. Mayo ClinProc 2006; 81; 353-373. Thomas MK, Lioyd-Jones DM. Hypovitaminosis D in medical inpatients. N Eng J Med. 1998; 338; 777-783.

6. Introductioncontd… • A common clinical practice to treat vitamin D deficiency is with 50,000 International Units (IU) of vitamin D2 orally once weekly for 6 to 12 weeks, and then 800 to 1000 IU of vitamin D3 daily thereafter. However, the efficacy of this practice has not been rigorously established. • In a study by Malabanan et al, in 35 patients with 25-OH vitamin D levels between 10ng/ml to 25ng/ml, vitamin D rose by 109% after treatment with vitamin D2 50,000 IU/week for a total of 8 weeks. Malabanan A. Redefining vitamin D insuficiency. The Lancet. 1998; 351; 805-806.

7. Introductioncontd… • However, in another study by Pepper et al, only 13% of subjects achieved vitamin D sufficiency (25-OH vitamin D>30ng/ml) when treated with vitamin D2 50,000 IU/week for a total of 8 weeks. • In another study, in healthy young and middle-aged adults, 100% of subjects achieved vitamin D sufficiency when treated with 1000 IU of vitamin D3/day for 12 weeks. Pepper KJ. Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. EndocrPract. 2009; 15; 95-103 Tangpricha V. Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health. Am J ClinNutr. 2003; 77; 1478-1483

8. Introductioncontd… • Vitamin D is a fat-soluble vitamin and it has been postulated that fat increases vitamin D absorption. • In a short report by Mulligan et al, in 17 patients with a mean baseline 25-OH vitamin D level of 30.5 ng/ml, administration of vitamin D with the largest meal improved absorption and resulted in higher serum levels of vitamin Dcompared to taking it on an empty stomach or with a small meal. Mulligan GB. Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D. Journal of Bone and Mineral Research. 2010; 25; 928-930.

9. Introductioncontd… • Other studies, however, have shown that fat is not required for vitamin D to be bioavailable. Pepper KJ. Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. EndocrPract. 2009; 15; 95-103 Hollander D. Vitamin D3 intestinal absorption in vivo: influence of fatty acids, bile salts, and perfusate pH on absorption. Gut. 1978; 19; 267-272.

10. Study • This study was conducted to evaluate the efficacy of different dosage forms of vitamin D in treating patients with vitamin D deficiency or insufficiency, and also to evaluate the effect of food on vitamin D absorption.

11. StudyDesign • This study was approved by the Institutional Review Board (IRB) through Mercy Hospital of Buffalo. • Study took place at Buffalo Rheumatology. • Subjects with 25-OH vitamin D deficiency or insufficiency (levels ≥10 and <30ng/ml) were recruited in this study. • Approximately 240 subjects were planned to be enrolled over a period of 12-18 months (30 subjects in each group).

12. StudyDesigncontd… • Subjects were randomly assigned to one of the following 4 treatment groups: • Vitamin D3 1000 IU/day • Vitamin D3 2000 IU/day • Vitamin D3 4000 IU/day • Vitamin D2 50,000 IU/week • Each group was further divided into two subgroups with vitamin D administered either FASTING or with the LARGEST MEAL of the day.

13. StudyDesigncontd… • Subjects had 2 visits and participation lasted 12 weeks. • At the first visit (Screening/Baseline), education was given regarding the protocol. • Subjects who agreed to participate signed an informed consent.

14. StudyDesigncontd… • Demographic information was obtained along with the medical history and current medications. • 12 weeks of study medication was given along with the instructions on dosing. • A lab script was provided for vitamin D reassessment at 12 weeks.

15. StudyDesigncontd… • 2nd visit (final visit) took place at the end of 12 weeks. • Compliance was ascertained by pill counts at the final visit. • Adverse events were captured at the final visit. • Deficient subjects at the end of 12 weeks were given prescription for vitamin D treatment.

16. StudyDesigncontd… • Study began in Jan, 2011 and 235 subjects had completed their study by the end of Jan, 2012. • Out of 235 subjects • 34 were lost to the follow-up or withdrew from the study. • 15 patients were excluded from the study due to low compliance (<80%) and early or late labs. • 186 subjects were included in this interim analysis.

17. EndPoints • Primary endpoint: • % increase in 25-OH vitamin D levels from baseline. • Secondary end point: • % of subjects achieving normal vitamin D levels (≥30ng/dl). • Absolute increase in vitamin D from baseline. • Results in each group were compared to each other.

18. InclusionCriteria • Men and women were included. • Age ≥18. • Vitamin D levels ≥10 and <30ng/ml.

19. ExclusionCriteria • Vitamin D levels <10ng/ml. • Malabsorption syndromes. • Intestinal bypass. • Uncontrolled cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine, or GI disease. • History of cancer within the last 5 years • (except non-melanoma skin cancers and cervical carcinoma in situ)

20. StatisticalAnalysis • Paired t-test was used for statistical analysis of data within each group. • Analysis of Variance (ANOVA) was used to compare data across the various groups. • P-value of ≤0.05 was deemed as statistically significant.

21. Demographics

22. Demographicscontd… Population count

23. Demographics contd…

24. Demographicscontd…

25. FiveBMIgroups

26. SixAgegroups

27. Four1stVitamin D groups

28. Results

29. % of subjects with 2ndVitamin D≥30

30. Absoluteincreaseinvitamin D

31. Fastingvs Meals

32. SubgroupAnalysis

33. SubgroupAnalysis

34. Subgroupanalysis • Subgroup analysis was also done on the basis of • BMI • Age • 1st vitamin D levels.

35. BMI % Increase in Vitamin D

36. BMIcontd… • Using Pearson correlation, significant but weak association was noticed between BMI and 2nd vitamin D levels (correlation coefficient -0.22), indicating that as the BMI increases vitamin D levels tend to decrease.

37. Age

38. 1stVitamin D levels • Patients with the lowest 1st vitamin D levels had the highest % increase of 183% (P-value=0.001). • % increase was only 41% in patients with highest 1st vitamin D levels (P-value <0.001).

39. 1stvitamin D levels

40. Conclusion • In patients with vitamin D deficiency or insufficiency, 50,000 IU/week of 25-OH vitamin D2 for a period of 12 weeks was most effective in achieving vitamin D sufficiency. • Food did not affect the vitamin D absorption in 1000D3, 2000D3 and 50,000D2 IU groups, however it did affect the absorption in 4000D3 IU group.

41. Conclusion • Patients with the highest BMI achieved lowest vitamin D level, thus suggesting the need for robust treatment in this patient population. • Patients with the highest 1st vitamin D level had lowest % increase in their vitamin D after treatment; this could be due to the plateau effect that occurs as the vitamin D levels tend to increase.

42. Limitations • Lack of placebo arm. • Study was not blinded. • Follow up data is not available for patients who did not achieve vitamin D sufficiency. • Additional study needs to be done to evaluate the vitamin D dosage required for maintaining vitamin D sufficiency.

43. Acknowledgment • Dr. Khalid J. Qazi • Buffalo Rheumatology staff • Mary Brennan, RN, MS • Tammi Kirsch, LPN • Jim Hatem

44. THANKS