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, PGY3Joseph Grisanti, MD

June 7th, 2012

University at BuffaloThe state University of New York

IntroductionLow 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 Clin Nutr; 2004; 80; 1678-1688.

Introduction contd…Vitamin D deficiency has been associated with Cancers Hypertension Cardiovascular diseases

Spina CS, Tangpricha V. Vitamin D and cancer. Anticancer Res. 2006; 26; 2515-2524Pilz S, Vitamin D status and arterial hypertension. A systematic review. Nat Rev Cardiol. 2009; 6; 621-630

Giovannucci E. 25-hydroxyvitamin D and risk of myocardial infarction in men. A prospective study. Arch Intern Med; 2008; 168; 1174-1180.

Introduction contd…Vitamin D deficiency has also been linked with Multiple sclerosis Rheumatoid arthritisType 1 diabetes mellitus

Munger KL. 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.

Introduction contd…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 Clin Proc 2006; 81; 353-373.

Thomas MK, Lioyd-Jones DM. Hypovitaminosis D in medical inpatients. N Eng J Med. 1998; 338; 777-783.

Introduction contd…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.

Introduction contd…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. Endocr Pract. 2009; 15; 95-103Tangpricha V. Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health. Am J Clin Nutr. 2003; 77; 1478-1483

Introduction contd…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 D compared 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.

Introduction contd…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. Endocr Pract. 2009; 15; 95-103Hollander D. Vitamin D3 intestinal absorption in vivo: influence of fatty acids, bile salts, and perfusate pH on absorption. Gut. 1978; 19; 267-272.

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.

Study Design 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).

Study Design contd…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.

Study Design contd…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.

Study Design contd…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.

Study Design contd…

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.

Study Design contd…Study began in Jan, 2011 and 235 subjects had completed their study by the end of Jan, 2012.

Out of 235 subjects34 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.

End Points

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.

Inclusion Criteria

Men and women were included.

Age ≥18.

Vitamin D levels ≥10 and <30ng/ml.

Exclusion Criteria

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)

Statistical Analysis

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.

Demographics

Total Count 186

Mean Age (Years) 53

Mean weight (Lbs) 189

Mean BMI 30.9

Mean 1st Vitamin D levels

22.9 ng/ml

Demographics contd…

Population count

1000D3 2000D3 4000D3 50,000D20

10

20

30

40

50

6050 48

4048

Vitamin D dosage

Num

ber

of P

atie

nts

Demographics contd…

1000

Mea

ls

1000

Fas

ting

2000

Mea

ls

2000

Fas

ting

4000

Mea

ls

4000

Fas

ting

50,00

0 Mea

ls

50,00

0 Fas

ting

0

10

20

30 2822 21

2719 21 24 24

Population count

Sub groups

Num

ber

of P

atie

nts

Demographics contd…

Demographics by Gender

Demographics by BMI

Male Female0

20406080

100120140160

38

148

Population Count

Num

ber

of P

atie

nts

Fastin

gM

eals

20406080

100 94 92Population Count

Num

ber

of

Pati

ents

Five BMI groups

<25 25-29.9 30-34.9 35-35.9 ≥400

10203040506070

36

5850

23 19

Population Count

BMI

Num

ber

of P

atie

nts

Six Age groups

<30 30-39 40-49 50-59 60-69 ≥700

102030405060

920

44 4651

16

Population Count

Age

Num

ber

of P

atie

nts

Four 1st Vitamin D groups

<15 15-19.9 20-24.9 25-29.90

20

40

60

80

100

9

33

57

87

Population Count

1st Vitamin D levels

Num

ber

of P

atie

nts

Results

1000D3 2000D3 4000D3 50,000D20%

20%40%60%80%

100%120%140%

25%35% 40%

117%

% Increase in Vitamin D

Vtamin D dosage

% I

ncre

ase

P

P-value<0.001

% of subjects with 2nd Vitamin D≥30

1000D3 2000D3 4000D3 50,000D20%

20%

40%

60%

80%

100%

120%

34%

63%70%

98%

Vitamin D dosage

% S

ubje

cts

Absolute increase in vitamin D

1000

D3

2000

D3

4000

D3

50,00

0D2

0.010.020.030.040.050.060.0

1st Vit D Mean2nd Vit D Mean

Vitamin D dosage

Vit

amin

D le

vels

(ng

/ml)

Fasting vs Meals

Fasting Meals25%30%35%40%45%50%55%60%65%70%75%

53%56%

% Increase in vitamin D

% I

ncre

ase

P-value=0.53

Subgroup Analysis

% Increase0%5%

10%15%20%25%30%35%

29%

21%

1000 MealsSeries2%

Inc

reas

e

P-valueP-value=0.19=0.19

9=0.19

pP-vP-value=0.19alue=0.19pPvalue=0.19

P-Value=0.19

% Increase30%

32%

34%

36%

38%

40%

36%35%

2000 MealsSeries22000 Fasting

% I

ncre

sae

P-P-value=0.74=0.79

Subgroup Analysis

% Increase0%

10%

20%

30%

40%

50%

60%51%

30% 4000 MealsSeries24000 Fasting

% I

ncre

ase

P-value=0.003

P-value=0.003

P-value=0.0030.11.32.53.74.96.17.38.59.7

% In

crea

se

P-value=0.27

% In-

crease

2 v 150%60%70%80%90%

100%110%120%130%

111%122%

50,000 MealsSeries250,000 Fasting%

Inc

reas

eP-value=0.27

P-P-value=0.27P-value=0.27value=0.27

Subgroup analysis

Subgroup analysis was also done on the basis ofBMIAge 1st vitamin D levels.

BMI

10%

20%

40%

60%

80%

100%

BMI < 25BMI 25-29.9BMI 30-34.9BMI 35-39.9BMI >= 40

BMI

% I

ncre

ase

P-value=0.003

% Increase in Vitamin D

BMI contd…

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.

0.0 20.0 40.0 60.0 80.00

20406080

100

2nd Vit D by BMI

2nd Vit D

Age

10%

10%20%30%40%50%60%70%80%

Age <30Age 30-39Age 40-49Age 50-59Age 60-69Age >=70

Age Groups

% I

ncre

ase

P-value=0.98

% Increase in Vitamin D

1st Vitamin 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).

1st vitamin D levels

10%

20%40%60%80%

100%120%140%160%180%200%

Vit D < 15Vit D 15-19.9Vit D 20-24.9Vit D 25-29.9

1st vitamin D

% I

ncre

ase

% Increase in Vitamin D

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.

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.

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.

Acknowledgment

Dr. Khalid J. QaziBuffalo Rheumatology staffMary Brennan, RN, MSTammi Kirsch, LPNJim Hatem

THANKS