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Bio-available Vitamin D following mega-doses (up to 500,000 IU) – Clinical trial due 2018

Change in Free 25(OH)D After High Dose in Vitamin D Deficient Postmenopausal Women

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified September 2015 by Sheffield Teaching Hospitals NHS Foundation Trust
Sponsor: Sheffield Teaching Hospitals NHS Foundation Trust
Collaborator::National Osteoporosis Society
Information provided by (Responsible Party):
Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02553044, First received: September 16, 2015

We currently use total 25(OH)D as a biomarker of vitamin D status. However, there is some debate as to whether total 25(OH)D is the best marker to use.

It has been suggested that free vitamin D may be better because it may be more biologically available.

There are also some uncertainties about how we treat vitamin D deficiency. A single dose is attractive because we know the patient has had the dose and there is no requirement for ongoing compliance, but we don't know what the best dose is to give. Also, recent studies have highlighted that high dose vitamin D supplementation may increase the risk of falling in older populations.

We think by studying how free vitamin D responds to different bolus doses is the best way address some of the current research gaps, including what is the best biomarker of vitamin D status, what is the mechanism of vitamin D toxicity and what is a safe bolus dose to treat deficiency.

We will study changes in total and free 25(OH)D, and also clinical response, to three different bolus doses of vitamin D (50 000IU, 150 000IU and 500 000IU) in 84 vitamin D deficient postmenopausal women, over a three month period with 5 study visits. We will also recruit 28 vitamin D sufficient postmenopausal women as a concurrent control group.

This will allow us to determine how total and free vitamin D change with bolus dosing and whether there is a disproportionate rise in free 25(OH)D with higher doses that may lead to hypercalcemia and falls.

Condition Intervention
Vitamin D Deficiency
Osteoporosis
Dietary Supplement: Cholecalciferol (Vitamin D3)

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Change in Free 25(OH)D After High Dose in Vitamin D Deficient Postmenopausal Women

Resource links provided by NLM:

MedlinePlus related topics: Vitamin D
Drug Information available for: Cholecalciferol Vitamin D
U.S. FDA Resources

Further study details as provided by Sheffield Teaching Hospitals NHS Foundation Trust:

Primary Outcome Measures:
Free 25(OH)D [ Time Frame: Baseline to visit 3 (5-7 days after administration) ] [ Designated as safety issue: No ]
Change in free 25(OH)D from baseline to visit 3 (5-7 days after administration)


Secondary Outcome Measures:
Proportion of total 25(OH)D to free 25(OH)D [ Time Frame: 5(+/-2) days, 28(+/-3) days and 84(+/-5) days ] [ Designated as safety issue: No ]
Between-group difference in proportion of serum free 25(OH)D to total 25(OH)D at 5, 28 days and 84 days

Bone turnover markers (Alkaline phosphatase, PINP, osteocalcin & CTX) [ Time Frame: 5(+/-2) days, 28(+/-3) days and 84(+/-5) days ] [ Designated as safety issue: No ]
Between group difference in biochemical markers of bone turnover at 5, 28 and 84 days

Muscle function tests [ Time Frame: 5(+/-2) days, 28(+/-3) days and 84(+/-5) days ] [ Designated as safety issue: No ]
Between group difference in muscle function tests at 5, 28 and 84 days

Estimated Enrollment: 112
Study Start Date: October 2015
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 50 000IU Vitamin D3
50 000IU oral vitamin D3 (cholecalciferol) administered at baseline only.
Dietary Supplement: Cholecalciferol (Vitamin D3)
Oral vitamin D3 doses made up using 50 000IU ampules of vitamin D3 dissolved in 1ml of olive oil.
Other Name: Invita D3
Experimental: 150 000IU Vitamin D3
150 000IU oral vitamin D3 (cholecalciferol) administered at baseline only.
Dietary Supplement: Cholecalciferol (Vitamin D3)
Oral vitamin D3 doses made up using 50 000IU ampules of vitamin D3 dissolved in 1ml of olive oil.
Other Name: Invita D3
Experimental: 500 000IU Vitamin D3
500 000IU oral vitamin D3 (cholecalciferol) administered at baseline only.
Dietary Supplement: Cholecalciferol (Vitamin D3)
Oral vitamin D3 doses made up using 50 000IU ampules of vitamin D3 dissolved in 1ml of olive oil.
Other Name: Invita D3
No Intervention: Concurrent Control
Control group to receive no intervention.

Detailed Description:
The most commonly used measurement of vitamin D status is serum 25-hydroxyvitamin D (25(OH)D). However there is no clear consensus on the level of 25(OH)D required to protect against adverse effects of deficiency.

One approach is to define deficiency is the level of 25(OH)D at which there is a secondary physiological response, such as a rise in parathyroid hormone. However, this approach has not yielded a clear answer. Total 25(OH)D below 30nmol/l is not always associated with an increased parathyroid hormone (PTH) response, and total 25(OH)D and PTH do not always respond to vitamin D supplementation (Shibli-Rahhal & Paturi 2014). This suggests that total 25(OH)D measurement may not be the best biological marker of vitamin D status.

Vitamin D and its metabolites are bound to proteins in the circulation: around 85-90% of 25(OH)D is bound to vitamin D binding protein (DBP), 10-15% is bound to albumin, and less than 1% is in the free form. DBP protects 25(OH)D from degradation and allows a circulating store to accumulate.

The free hormone hypothesis suggests that only the unbound 'free' portion of protein bound hormones is biologically active, and that this should be measured for the accurate assessment of hormone availability. Calculated free 25(OH)D concentrations have been shown to be better correlated to bone mineral density (BMD) than total 25(OH)D in a healthy population (Powe et al., 2011) and to be more closely related to PTH in patients with end stage renal disease (Bhan et al., 2012).

The binding capacity of DBP may be overwhelmed in some situations. Sanders et al., (2010) treated women with an oral dose of 500,000 IU annually for 3 years and found an increase in the risk of falls and fractures that was particularly marked in the three month period after each dose. It has been proposed that there was vitamin D toxicity and possible hypercalcaemia during this period due to the binding capacity of DBP being overwhelmed by the large increase in 25(OH)D with a relatively greater increase in free 25(OH)D. However, free vitamin D and calcium were not measured in the study, so there is not yet evidence to support this hypothesis.

We will study changes in total and free 25(OH)D, and clinical response to three different bolus doses of vitamin D (50,000 units, 150,000 units and 500,000 units) in 84 vitamin D deficient (<30nmol/l) postmenopausal women over three months. This will allow us to determine how free and total 25(OH)D change with bolus dosing and whether there is a disproportionately high rise in free 25(OH)D with higher doses. This will also allow us to better understand what the optimum bolus dose for treatment of vitamin D deficiency is and whether free 25(OH)D may be a better marker of vitamin D status in some situations.

Aims of the study:

To determine the effect of three different vitamin D bolus doses on free 25(OH)D and total 25(OH)D in vitamin D deficient post-menopausal women.
To determine the effect of different vitamin D bolus doses on parameters of calcium metabolism, bone turnover markers and physical function in vitamin D deficient post-menopausal women.
Eligibility

Ages Eligible for Study: 55 Years and older
Genders Eligible for Study: Female
Accepts Healthy Volunteers: Yes
Criteria
Inclusion Criteria:

Caucasian
25(OH)D < 30nmol/l for treatment groups or 25(OH)D >50nmol/l for control group
BMI between 20 kg/m2 and 30kg/m2
55 years and over and postmenopausal (at least 5 years since last menstrual period)
Able and willing to participate in the study and provide written informed consent.
Exclusion Criteria:

History of any long term immobilization (duration greater than three months)
Pre-diagnosed diabetes mellitus
High trauma fracture or low trauma fracture less than one year prior to recruitment
History of or current conditions known to affect vitamin D or bone metabolism, including:
Chronic renal disease Malabsorption syndromes Diagnosed endocrine disorders Hypercalcaemia Diagnosed restrictive eating disorder

Use of medications or treatment known to affect vitamin D or bone metabolism such as bisphosphonates or anti-epileptic medication.
Alcohol intake of greater than 21 units per week
Holiday with significant sunlight exposure in the last six weeks
Planned sun holiday within study period
Abnormal clinical laboratory parameters that are assessed as clinically significant by the PI.
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02553044

Contacts
Contact: Simon D Bowles, MMedSci, MRes 0114 2266548 sbowles1@sheffield.ac.uk
Contact: Jennifer Walsh, MBChB, PhD 0114 2714705 j.walsh@sheffield.ac.uk

Sponsors and Collaborators
Sheffield Teaching Hospitals NHS Foundation Trust
National Osteoporosis Society
Principal Investigator: Jennifer Walsh, MBChB, PhD University of Sheffield

Publications:

  • Shibli-Rahhal A, Paturi B. Variations in parathyroid hormone concentration in patients with low 25 hydroxyvitamin D. Osteoporos Int. 2014 Jul;25(7):1931-6. doi: 10.1007/s00198-014-2687-4. Epub 2014 Mar 20.
  • Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010 May 12;303(18):1815-22. doi: 10.1001/jama.2010.594. Erratum in: JAMA. 2010 Jun 16;303(23):2357.
  • Powe CE, Ricciardi C, Berg AH, Erdenesanaa D, Collerone G, Ankers E, Wenger J, Karumanchi SA, Thadhani R, Bhan I. Vitamin D-binding protein modifies the vitamin D-bone mineral density relationship. J Bone Miner Res. 2011 Jul;26(7):1609-16. doi: 10.1002/jbmr.387. Erratum in: J Bone Miner Res. 2012 Jun;27(6):1438.
  • Bhan I, Powe CE, Berg AH, Ankers E, Wenger JB, Karumanchi SA, Thadhani RI. Bioavailable vitamin D is more tightly linked to mineral metabolism than total vitamin D in incident hemodialysis patients. Kidney Int. 2012 Jul;82(1):84-9. doi: 10.1038/ki.2012.19. Epub 2012 Mar 7.

Responsible Party: Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02553044 History of Changes
Other Study ID Numbers: STH18850
Study First Received: September 16, 2015
Last Updated: September 16, 2015
Health Authority: United Kingdom: National Institute for Health Research

Additional relevant MeSH terms:
Vitamin D Deficiency, Avitaminosis, Deficiency Diseases, Malnutrition, Nutrition Disorders, Cholecalciferol
Ergocalciferols, Vitamin D, Vitamins, Bone Density Conservation Agents, Growth Substances, Micronutrients. Pharmacologic Actions, Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 17, 2015

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