The Effect of Vitamin D Supplementation on Calcium Excretion in Thalassemia: a Dose Response Study
The Effect of Vitamin D Supplementation on Calcium Excretion in Thalassemia: a Dose Response Study
The purpose of this pilot study is to determine the effect of various doses of vitamin D
 supplementation on vitamin D stores and calcium excretion in the urine in subjects with
 Thalassemia Major (TM). Subjects with TM are routinely placed on vitamin D supplements
 because they frequently have osteoporosis (a condition in which bone tissue thins and loses
 density and strength) and low vitamin D stores. The amount of vitamin D supplementation that
 is required to raise vitamin D stores in optimal levels is not known in TM, and will be
 determined in this study. Finally, a recent study in TM has linked blood vitamin D levels to
 urine calcium excretion, which is a risk factor for kidney stones. Therefore, we want to
 determine changes in calcium excretion with various vitamin D doses and with increasing
 vitamin D stores. We plan to test 3 doses of vitamin D for 3 months in children and adults
 with TM. Changes in vitamin D blood levels and urinary calcium will be determined. The
 results of this pilot study will be used in future studies that will examine the effect of
 various doses of vitamin D supplementation in the treatment of osteoporosis in TM.
Specific Aim: To determine the effect of various doses of vitamin D supplementation on serum
 concentration of 25 hydroxy vitamin D (25OHD) and urinary calcium excretion in adults and
 children with TM.

 Hypothesis: Vitamin D supplementation at doses that result in serum 25OHD levels >30 ng/ml
 result in high rates of hypercalciuria (i.e. increased urinary calcium excretion) in children
 and adults with TM.

 The pilot study will be performed at Weill Cornell Medical College, Payson 695.

 -  Children and adults with TM, will be divided into 4 groups: "standard" vitamin D dose
 (equivalent to 400 IU/day), "intermediate" vitamin D dose (equivalent to 1000 IU/day),
 "high" vitamin D dose (equivalent to 2,000 IU/day) and a "placebo" group that will
 receive an inactive ingredient. 10 subjects will be assigned to each group. The duration
 of the study will be 3 months.

 -  While some studies found no difference between vitamin D2 and D3, others suggest that
 vitamin D3 may be more advantageous in restoring 25 OHD concentrations. For these
 reasons, vitamin D3 will be used in this protocol.

 -  Study schedule with study interventions and frequencies is set out below (see table).
 All 4 groups will adhere to the same schedule. After obtaining consent, subjects will
 have a "Baseline Visit", which will include: 1) a complete physical examination; 2)
 laboratory evaluation that includes measurement of 25OHD, which is the major circulating
 form of vitamin D and reflects the body's vitamin D stores. Additional blood and urine
 samples will be obtained for measurement of urinary calcium excretion and serum Calcium
 and parathyroid hormone (PTH); and 3) Dietary calcium intake questionnaire. 4) Start of
 study medication.

 -  Subjects will then return every 2-4 weeks for routine blood transfusions and as required
 for the management of Thalassemia. To ensure compliance, study medications will be
 administered by study personnel during these routine visits. Vitamin D supplies will be
 packaged according to one week worth requirement, i.e. as 1,000 IU/day x 7days=7,000 IU
 for the "intermediate" vitamin D group. The dose that will be administered during these
 visits will depend on the interval between transfusions, i.e. 7,000 IU x 2weeks, for a
 subject of the "intermediate" dose who is transfused every two weeks.

 -  At the end of 3 month treatment, subjects will have a final visit, that is also
 scheduled to coincide with a routine transfusion visit. Subjects will have the same
 evaluation and procedures as in "Baseline Visit" : 1) a complete physical examination;
 2) fasting laboratory evaluation that includes measurement of 25OHD, urinary calcium
 excretion and serum Calcium and PTH; and 3) Dietary calcium intake questionnaire.

 -  Subjects will be asked to take calcium supplementation at the dose of 500 mg daily for
 the 6-8 year old and 1,000 mg daily for the 9-18 year old subjects. This intervention
 will ensure adequate calcium intake in both groups.

 All labs will be processed at the CTSC Core Lab. Study meds will be distributed by the
 central pharmacy. Investigational drug will be administered by study personnel during the
 transfusion visits to ensure compliance.

 Eligible subjects will be assigned to a study group following a block type of enrollment. To
 ensure an equal, or near equal sex and age distribution, study groups will be matched
 according to sex and age. Half of the subjects in each group will be composed of pediatric
 subjects and the other half will be composed of adult subjects.

 Study Schedule and Procedures:

 -  Baseline visit: Physical Exam, 25OHD, Intact PTH & Serum Calcium, 24 hr & spot urine
 collection for Ca/Crea, Calcium intake questionnaire, Vitamin D Supplementation/Placebo.

 -  Every 2-4 weeks: Administration of Vitamin D/Placebo

 -  3 Month Visit: Physical Exam, 25OHD, Intact PTH & Serum Calcium, 24 hr & spot urine
 collection for Ca/Crea, Calcium intake questionnaire, and Vitamin D Supplementation/
 Placebo.

 Primary study endpoint:

 Changes in 25OHD concentrations and calcium excretion with the various vitamin D3 doses will
 be determined at the end of the study and constitute the primary endpoints.
Inclusion Criteria:

 -  Thalassemia Major (TM)

 -  25 OHD: 15-29 ng/ml

 -  Age 6 to 60 years

 -  Albumin corrected serum Calcium: Normal (8.5-10.5 mg/dl)

 Exclusion Criteria:

 -  Other thalassemia syndromes

 -  25 OHD concentrations < 15 ng/ml or ≥30 ng/ml

 -  Subjects younger than 6 years

 -  Hypoparathyroidism

 -  Abnormal albumin corrected serum Ca (i.e. total calcium <8.5 or > 10.5 mg/dl)

 -  Medications that may adversely affect vitamin D metabolism (anticonvulsants) or
 absorption

 -  End stage renal, heart, or liver disease

 -  History of Nephrolithiasis or Nephrocalcinosis

 -  Diseases associated with hypercalciuria (ie. Sarcoidosis, Cushing syndrome, and Wilson
 disease to name a few)