Ignite Creation Date:
2024-05-05 @ 5:16 PM
Last Modification Date:
2024-10-26 @ 9:30 AM
Study NCT ID:
NCT00427804
Status:
COMPLETED
Last Update Posted:
2013-02-04
First Post:
2007-01-25
Brief Title:
Tumor Necrosis Factor Decreases Vitamin D Dependant Calcium Absorption
Sponsor:
Atlanta VA Medical Center
Organization:
Atlanta VA Medical Center
Study Overview
Official Title:
Tumor Necrosis Factor-α Induces Vitamin D Resistance in Small Intestinal Calcium Absorption
Status:
COMPLETED
Status Verified Date:
2013-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This study is a pilot study to determine whether patients with TNFα excess have decreased calcium absorption in response to calcitriol 125-dihydroxyvitamin D the active form of vitamin D compared to normal controls This initial pilot study is being done to determine if it is feasible to conduct a study where TNFα could be blocked eg by anti-TNFα therapy such as Enbrel or Remicade to improve vitamin D dependant calcium absorption and thus bone health
Detailed Description:
Vitamin D is important for the maintenance of normal calcium homeostasis by improving the efficacy of calcium absorption from the small intestine The efficacy of calcium absorption is decreased with aging menopause and other inflammatory states Subjects who have low intestinal absorption of calcium are at risk for developing osteoporosis and fractures Early data suggests that patients with rheumatoid arthritis RA and Crohns disease appear to have decreased calcium absorption Patients with RA and Crohns disease have elevated levels of TNFα in local tissues and systemically which may be causing resistance to vitamin D dependant calcium absorption
Recently a new vitamin D dependant calcium channel important for calcium absorption has been discovered in the small intestine called Transient Receptor Potential Vallinoid type 6 TRPV6 We have some pre-clinical data in rats to suggest that TNFα has a role in inhibiting the expression of this protein by decreasing the induction of this protein in response to vitamin D treatment
HYPOTHESIS
Subjects with disease conditions that result in elevated TNFα have vitamin D resistance and inability to increase calcium absorption with increasing concentrations of calcitriol
STUDY DESIGN
Subjects The study will be conducted at the Emory GCRCEmory Clinic and VA clinical research center Study participants will be recruited from the Atlanta Veterans Administration Medical Center VAMC and Emory Clinics for participation in the study according to the following inclusion and exclusion criteria
Inclusion Males age 18 to 50 history of Crohns disease or Rheumatoid Arthritis cases or healthy individuals controls
Exclusion Subjects already taking activated vitamin D medications such as calcitriol Zemplar Hectoral vitamin D deficiency defined as 25OHD 20 ngml post-menopausal women absence of menses for greater than 6 months by history or FSH level 20 history of nephrolithiasis history of hypercalcemia or hypercalciuria short bowel disease glucocorticoid use use of osteoporosis medication bisphosphonate calcitonin or teriparatide chronic kidney disease calculated GFR 60 mlmin173 m2 history of hyperparathyroidism PTH greater than upper limit of normal or hypoparathyroidism PTH below lower limit of normal
Procedures
Screening Phase Case subjects will be identified from Rheumatology and Gastroenterology clinics from the VA or Emory Clinic The subjects doctors will give the patient a brochure of the study with the study investigators name and phone number to contact There will also be advertisements in the Rheumatology and Gastroenterology clinics to recruit subjects for the study Control subjects will be identified by postings at the VA hospital or at Emory Clinic in designated areas for research postings
The subject will initiate contact with the study personnel by calling the number on the advertisement or brochure The study investigator will pre-screen the subject on the phone to see if the subject is eligible for entry into the study If the subject remains eligible the subject will be invited to the VA clinical research center or Emory GCRCEmory Clinic for informed consent
Screening Visit The study investigator will review the inclusion and exclusion criteria with each subject If the subject agrees to participate in the study the subject will sign the informed consent and undergo baseline laboratory investigations for total calcium parathyroid hormone PTH 25-hydroxyvitamin D comprehensive panel including renal function 24-hour urine collection for calcium and creatinine clearance Subjects will be counseled to take no more than 600 mg of calcium daily and no more than 400 IU a day of vitamin D The subjects will be instructed on how to complete a three day food diary for future visits
They will be given a schedule to return for the following visits
Visit 1 baseline fractional absorption of calcium FCA Subjects will return to the clinical research center in a fasting state for a baseline FCA test see specific methods in the following section Subjects will return their three day food diary record Subjects will also have blood drawn for comprehensive panel including calcium and renal function 125-dihydroxyvitamin D PTH level and serum TNFα The subjects will be given calcitriol 025 mcg PO BID to be taken for 7 days
Visit 2 FCA on low dose calcitrol 025 mcg PO BID Subjects will take their morning dose of calcitriol 8 am on the day of visit 2 Subjects will come to the clinic in a fasting state They will return their 3 day food diary records A repeat FCA will be performed Subjects will also have blood drawn for comprehensive panel including calcium and renal function 125-dihydroxyvitamin D PTH level and serum TNFα After the test is completed the subjects will be given calcitriol 050 mcg PO BID to be taken for 7 days They will be scheduled to return to the clinical research center within 20 days after a minimum 7 day washout period
Visit 3 FCA on high dose calcitriol 050 mcg PO BID Subjects will take their morning dose of calcitriol at 8 am on the day of visit 3 Subjects will come to the clinic in a fasting state They will return their 3 day food diary records A repeat FCA will be performed Subjects will also have blood drawn for comprehensive panel including calcium and renal function 125-dihydroxyvitamin D PTH level and serum TNFα
Fractional absorption of calcium FCA procedure Subjects will come to the clinic after an overnight fast After voiding the fasting urine a 24 hour urine collection will begin Each subject will receive a standard breakfast see FCA diet section which will contain approximately 211 mg of calcium and 45 IU of vitamin D Oral 43Ca will be administered after the patient has drunk the milk 19 ml will be drawn from a sterile 43Ca calcium chloride vial with a syringe and will be injected in 4 ounces of distilled water The subject will drink the glass of water The glass will be rinsed twice with 4 ounces of distilled water and the subject will drink each rinse
27 ml of 42Ca will be drawn from a sterile 42Ca calcium chloride vial with a sterile hypodermic syringe The solution will be injected into the patient intravenously with an IV catheter and flushed with 5 ml of normal saline The intravenous calcium will be infused within 30 minutes of ingestion of the oral calcium
The subject will be discharged from the clinical research center and will continue with their 24 hour urine collection The following morning the subject will return the 24 hour urine collection to the research clinic The subject will be advised to not eat for at least 4 hours after the breakfast meal
Recently a new vitamin D dependant calcium channel important for calcium absorption has been discovered in the small intestine called Transient Receptor Potential Vallinoid type 6 TRPV6 We have some pre-clinical data in rats to suggest that TNFα has a role in inhibiting the expression of this protein by decreasing the induction of this protein in response to vitamin D treatment
HYPOTHESIS
Subjects with disease conditions that result in elevated TNFα have vitamin D resistance and inability to increase calcium absorption with increasing concentrations of calcitriol
STUDY DESIGN
Subjects The study will be conducted at the Emory GCRCEmory Clinic and VA clinical research center Study participants will be recruited from the Atlanta Veterans Administration Medical Center VAMC and Emory Clinics for participation in the study according to the following inclusion and exclusion criteria
Inclusion Males age 18 to 50 history of Crohns disease or Rheumatoid Arthritis cases or healthy individuals controls
Exclusion Subjects already taking activated vitamin D medications such as calcitriol Zemplar Hectoral vitamin D deficiency defined as 25OHD 20 ngml post-menopausal women absence of menses for greater than 6 months by history or FSH level 20 history of nephrolithiasis history of hypercalcemia or hypercalciuria short bowel disease glucocorticoid use use of osteoporosis medication bisphosphonate calcitonin or teriparatide chronic kidney disease calculated GFR 60 mlmin173 m2 history of hyperparathyroidism PTH greater than upper limit of normal or hypoparathyroidism PTH below lower limit of normal
Procedures
Screening Phase Case subjects will be identified from Rheumatology and Gastroenterology clinics from the VA or Emory Clinic The subjects doctors will give the patient a brochure of the study with the study investigators name and phone number to contact There will also be advertisements in the Rheumatology and Gastroenterology clinics to recruit subjects for the study Control subjects will be identified by postings at the VA hospital or at Emory Clinic in designated areas for research postings
The subject will initiate contact with the study personnel by calling the number on the advertisement or brochure The study investigator will pre-screen the subject on the phone to see if the subject is eligible for entry into the study If the subject remains eligible the subject will be invited to the VA clinical research center or Emory GCRCEmory Clinic for informed consent
Screening Visit The study investigator will review the inclusion and exclusion criteria with each subject If the subject agrees to participate in the study the subject will sign the informed consent and undergo baseline laboratory investigations for total calcium parathyroid hormone PTH 25-hydroxyvitamin D comprehensive panel including renal function 24-hour urine collection for calcium and creatinine clearance Subjects will be counseled to take no more than 600 mg of calcium daily and no more than 400 IU a day of vitamin D The subjects will be instructed on how to complete a three day food diary for future visits
They will be given a schedule to return for the following visits
Visit 1 baseline fractional absorption of calcium FCA Subjects will return to the clinical research center in a fasting state for a baseline FCA test see specific methods in the following section Subjects will return their three day food diary record Subjects will also have blood drawn for comprehensive panel including calcium and renal function 125-dihydroxyvitamin D PTH level and serum TNFα The subjects will be given calcitriol 025 mcg PO BID to be taken for 7 days
Visit 2 FCA on low dose calcitrol 025 mcg PO BID Subjects will take their morning dose of calcitriol 8 am on the day of visit 2 Subjects will come to the clinic in a fasting state They will return their 3 day food diary records A repeat FCA will be performed Subjects will also have blood drawn for comprehensive panel including calcium and renal function 125-dihydroxyvitamin D PTH level and serum TNFα After the test is completed the subjects will be given calcitriol 050 mcg PO BID to be taken for 7 days They will be scheduled to return to the clinical research center within 20 days after a minimum 7 day washout period
Visit 3 FCA on high dose calcitriol 050 mcg PO BID Subjects will take their morning dose of calcitriol at 8 am on the day of visit 3 Subjects will come to the clinic in a fasting state They will return their 3 day food diary records A repeat FCA will be performed Subjects will also have blood drawn for comprehensive panel including calcium and renal function 125-dihydroxyvitamin D PTH level and serum TNFα
Fractional absorption of calcium FCA procedure Subjects will come to the clinic after an overnight fast After voiding the fasting urine a 24 hour urine collection will begin Each subject will receive a standard breakfast see FCA diet section which will contain approximately 211 mg of calcium and 45 IU of vitamin D Oral 43Ca will be administered after the patient has drunk the milk 19 ml will be drawn from a sterile 43Ca calcium chloride vial with a syringe and will be injected in 4 ounces of distilled water The subject will drink the glass of water The glass will be rinsed twice with 4 ounces of distilled water and the subject will drink each rinse
27 ml of 42Ca will be drawn from a sterile 42Ca calcium chloride vial with a sterile hypodermic syringe The solution will be injected into the patient intravenously with an IV catheter and flushed with 5 ml of normal saline The intravenous calcium will be infused within 30 minutes of ingestion of the oral calcium
The subject will be discharged from the clinical research center and will continue with their 24 hour urine collection The following morning the subject will return the 24 hour urine collection to the research clinic The subject will be advised to not eat for at least 4 hours after the breakfast meal
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None