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Trial registered on ANZCTR


Registration number
ACTRN12609000246280
Ethics application status
Approved
Date submitted
17/04/2009
Date registered
12/05/2009
Date last updated
6/07/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
The role of 25-hydroxyvitamin D in insulin resistance and inflammation in patients with Chronic Kidney Disease: A randomised controlled trial.
Scientific title
The role of 25-hydroxyvitamin D in insulin resistance and inflammation in patients with Chronic Kidney Disease: A randomised controlled trial.
Secondary ID [1] 262427 0
Nil.
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Kidney Disease Stage 3 4621 0
Vitamin D deficiency 4622 0
Condition category
Condition code
Metabolic and Endocrine 4922 4922 0 0
Metabolic disorders
Inflammatory and Immune System 4923 4923 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cholecalciferol (vitamin D3) oral tablets (1000IU/25micrograms), 2 tablets/day for a total of 6 months. It was not felt to be ethical to randomise patients who were frankly vitamin D deficient. However, useful data can be obtained using the patients as their own controls. Specifically, results will be compared using paired T tests (baseline and end of study) to determine whether correction of overt deficiency is associated with an improvement in insulin sensitivity and inflammatory burden. The magnitude of response (presuming a positive effect) will be compared in general terms to the size of effect in the 2 arms of the randomised study.
Intervention code [1] 4382 0
Treatment: Drugs
Comparator / control treatment
Placebo - oral sugar pill (same compound vehicle as active treatment) 2 tablets/day for a total of 6 months.
Control group
Placebo

Outcomes
Primary outcome [1] 5770 0
Improvement in insulin sensitivity measured by hyperinsulinaemic euglycaemic clamp.
Timepoint [1] 5770 0
After 6 months of tablet intervention.
Secondary outcome [1] 241725 0
Changes in Nuclear Factor-kappaB p65 (NFKB-p65) binding activity in Peripheral Blood Mononuclear Cells (PBMCs). PBMCs will be extracted from whole blood using Ficoll-Paque gradient, and protein extracted thereafter. Protein activity will be assessed using a commercially available Enzyme Linked Immunosorbant Assay(ELISA).
Timepoint [1] 241725 0
After 6 months of tablet intervention.
Secondary outcome [2] 241726 0
Change in circulating Interleukin-1beta (IL-1b), Interleukin-6 (IL-6) and Tumour Necrosis Factor alpha (TNFa) concentrations, as assessed using ELISA analysis of patient plasma.
Timepoint [2] 241726 0
After 6 months of tablet intervention.
Secondary outcome [3] 241727 0
Change in serum osteocalcin and adiponectin concentrations, as assessed using ELISA analysis of patient plasma.
Timepoint [3] 241727 0
After 6 months of tablet intervention.
Secondary outcome [4] 241728 0
Changes in endothelial function (Brachial Artery Reactivity) and aortic compliance (Pulse Wave Velocity).
Timepoint [4] 241728 0
After 6 months of tablet intervention.
Secondary outcome [5] 241729 0
Assessment of incremental rise in serum 25-hydroxyvitamin D related to non-lean mass (as quantified by Dual Energy X-ray Absorptiometry (DXA)).
Timepoint [5] 241729 0
After 6 months of tablet intervention.

Eligibility
Key inclusion criteria
Chronic Kidney Disease (CKD) stage 3 (estimated glomerular filtration rate (eGFR)20-59ml/min/1.73m2, calculated using Modified Diet in Renal Disease (MDRD) formula). Age 18 or over.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Unable or unwilling to give informed consent. Estimated glomerular filtration rate <20 or >60ml/min/1.73m2. Life expectancy less than 6 months. Predicted to start dialysis within 6 months. Current involvement in other research study. Organ transplant recipient. Active inflammatory/infectious process or recent (<1 month) use of anti-inflammatory drugs. Use of oral hypoglycaemic medication. Current or recent (<3 months prior) use of; vitamin D products, glucocorticoids, anti-convulsants, barbiturates, hormone therapy. Chronic or active pathology resulting in liver or pancreatic disease. Malabsorptive state or lactose intolerant. Active endocrine disorder; thyrotoxicosis, Cushing’s, acromegaly,phaeochromocytoma. Serum corrected calcium >2.54mmol/L. Serum phosphate >1.49mmol/L

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Once a potential study participant has been identified and informed consent signed, they will undergo a baseline assessment, after which if they meet the eligibility criteria and have serum 25-hydroxyvitamin D levels >37nmol/L they will be randomised into one of two groups (1:1). To ensure allocation concealment, 'off-site' computer randomisation will be used.
At the time of enrollment patients will be issued a unique identification number consisting of a three-digit study number. The investigator will sequentially assign these numbers. Once assigned, the patients’ three-digit study number will not be re-used and will remain with the patient for the duration of the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be by permuted block and stratified for baseline Body Mass Index (BMI, <25 or >25) and diabetic status. Randomisation will be performed using a validated Microsoft Access based system available at Centre for Clinical Research Excellence Metabolic and Vascular Health, University of Queensland, that automates the random assignment of treatment group to randomisation numbers, based on the stratification data, permuted block size, and the generation of a randomisation code for the order in which to select each block.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Observiational arm recruited in parallel using the same entrance criteria, but if found to have 25-hydroxyvitamin D levels <37nmol/L will be non randomised and treated with cholecalciferol 2000IU/day
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
9/10/2009
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
51
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 4804 0
Charities/Societies/Foundations
Name [1] 4804 0
Princess Alexandra Hospital Private Practice Trust Fund Research Grant
Country [1] 4804 0
Australia
Funding source category [2] 267268 0
Commercial sector/Industry
Name [2] 267268 0
Roche Products Pty Ltd (Australia)
Country [2] 267268 0
Australia
Primary sponsor type
Individual
Name
A/Prof Nicole Isbel
Address
Department of Nephrology
Level 2 ARTS Building (31)
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102
Country
Australia
Secondary sponsor category [1] 4337 0
Hospital
Name [1] 4337 0
Princess Alexandra Hospital
Address [1] 4337 0
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102
Country [1] 4337 0
Australia
Other collaborator category [1] 644 0
Individual
Name [1] 644 0
Dr Will Petchey
Address [1] 644 0
Department of Nephrology
Level 2 ARTS Building (31)
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102
Country [1] 644 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6850 0
Princess Alexandra Hospital Human Research Ethics committee (PAH HREC)
Ethics committee address [1] 6850 0
Human Research Ethics Committee
Centres for Health Research
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102
Ethics committee country [1] 6850 0
Australia
Date submitted for ethics approval [1] 6850 0
16/04/2009
Approval date [1] 6850 0
22/05/2009
Ethics approval number [1] 6850 0
2009/097
Ethics committee name [2] 239482 0
University of Queensland Medical Research Ethics Committee
Ethics committee address [2] 239482 0
Human Ethics, Research and Research Training Division, Cumbrae-Stewart Building (#72), University of Queensland, BRISBANE, QLD 4072.
Ethics committee country [2] 239482 0
Australia
Date submitted for ethics approval [2] 239482 0
11/06/2009
Approval date [2] 239482 0
10/07/2009
Ethics approval number [2] 239482 0
2009001167

Summary
Brief summary
Chronic Kidney Disease (CKD) is associated with increased cardiovascular morbidity and mortality. Addressing traditional cardiac risk factors in this population does not ameliorate the disease burden to the
same extent as the background population. As such, novel risks are being explored.
Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis. The vitamin D receptor is found in almost all human tissues, and whilst it was once thought that only the kidneys metabolised vitamin D to its active form (calcitriol), other tissues (such as peripheral blood mononuclear
cells, PBMCs) are recognised as possessing the metabolising enzyme, raising the question of whether vitamin D effects are in part an auto/paracrine response, highlighting the importance of precursor availability.
Approximately 50% of patients with CKD stage 3 are vitamin D insufficient (measured as the serum precursor calcidiol). They have increased circulating inflammatory cytokines and are often sub-clinically insulin-resistant. These factors are known to be associated with cardiovascular risk, and are integrally linked. Indeed, Interleukin-1beta (IL-1b), Interleurkin-6 (IL-6)and Tumour Necrosis Factor alpha (TNFa)have been associated with pancreatic Beta-cell apoptosis, and diminished cellular insulin processing. In experimental models vitamin D can reduce the activation of the pro-inflammatory transcription factor Nuclear Factor-kappaB in various cell lines, and in isolated PBMCs vitamin D decreases production of IL-6 and TNFa. In vitro studies also suggest vitamin D may improve insulin receptor substrate phosphorylation and GLUT 4 translocation in skeletal muscle, together with direct effects on the pancreatic Beta-cells. Lastly, recent animal studies have implicated the vitamin D responsive bone protein osteocalcin in glucose metabolism, possibly through promotion of adiponectin production, an adipokine with known beneficial glycaemic properties.
This double-blinded trial will assess the benefit of vitamin D supplementation in early CKD to raise circulating calcidiol and improve insulin resistance, possibly through reduced inflammatory burden. Patients will be randomised to either vitamin D3 2000IU/day or placebo for 6 months.
At baseline and end-of-study a hyperinsulinaemic euglycaemic clamp study will be performed to assess peripheral insulin response and correlation with PBMC NF-kappaB activity and circulating inflammatory burden (as quantified
by IL-1b, IL-6, TNFa, known gene products of NF-KappaB). Osteocalcin, adiponectin and markers of bone turnover will also be assessed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29504 0
Address 29504 0
Country 29504 0
Phone 29504 0
Fax 29504 0
Email 29504 0
Contact person for public queries
Name 12751 0
A/Prof Nikky Isbel
Address 12751 0
Department of Nephrology
Level 2 ARTS Building (31)
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102
Country 12751 0
Australia
Phone 12751 0
+61 7 3240 2193
Fax 12751 0
+61 7 3240 5245
Email 12751 0
[email protected]
Contact person for scientific queries
Name 3679 0
A/Prof Nikky Isbel
Address 3679 0
Department of Nephrology
Level 2 ARTS Building (31)
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102
Country 3679 0
Australia
Phone 3679 0
+61 7 3240 2193
Fax 3679 0
+61 7 3240 5245
Email 3679 0
[email protected]

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