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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]

Nil.

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Chronic Kidney Disease Stage 3

Vitamin D deficiency

Condition category

Condition code

Metabolic and Endocrine

Metabolic disorders

Inflammatory and Immune System

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]

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]

Improvement in insulin sensitivity measured by hyperinsulinaemic euglycaemic clamp.

Timepoint [1]

After 6 months of tablet intervention.

Secondary outcome [1]

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]

After 6 months of tablet intervention.

Secondary outcome [2]

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]

After 6 months of tablet intervention.

Secondary outcome [3]

Change in serum osteocalcin and adiponectin concentrations, as assessed using ELISA analysis of patient plasma.

Timepoint [3]

After 6 months of tablet intervention.

Secondary outcome [4]

Changes in endothelial function (Brachial Artery Reactivity) and aortic compliance (Pulse Wave Velocity).

Timepoint [4]

After 6 months of tablet intervention.

Secondary outcome [5]

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]

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]

Charities/Societies/Foundations

Name [1]

Princess Alexandra Hospital Private Practice Trust Fund Research Grant

Address [1]

PA Foundation
Building 15
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba Qld 4102

Country [1]

Australia

Funding source category [2]

Commercial sector/Industry

Name [2]

Roche Products Pty Ltd (Australia)

Address [2]

Roche Products Pty Limited
4-10 Inman Road
Dee Why NSW 2099
Australia

Country [2]

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]

Hospital

Name [1]

Princess Alexandra Hospital

Address [1]

Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102

Country [1]

Australia

Other collaborator category [1]

Individual

Name [1]

Dr Will Petchey

Address [1]

Department of Nephrology
Level 2 ARTS Building (31)
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Princess Alexandra Hospital Human Research Ethics committee (PAH HREC)

Ethics committee address [1]

Human Research Ethics Committee
Centres for Health Research
Princess Alexandra Hospital 
199 Ipswich Road
Woolloongabba
QLD 4102

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

16/04/2009

Approval date [1]

22/05/2009

Ethics approval number [1]

2009/097

Ethics committee name [2]

University of Queensland Medical Research Ethics Committee

Ethics committee address [2]

Human Ethics, Research and Research Training Division, Cumbrae-Stewart Building (#72), University of Queensland, BRISBANE, QLD 4072.

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

11/06/2009

Approval date [2]

10/07/2009

Ethics approval number [2]

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

Address

Country

Phone

Fax

Email

Contact person for public queries

Name

A/Prof Nikky Isbel

Address

Department of Nephrology
Level 2 ARTS Building (31)
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102

Country

Australia

Phone

+61 7 3240 2193

Fax

+61 7 3240 5245

Email

nikky_isbel@health.qld.gov.au

Contact person for scientific queries

Name

A/Prof Nikky Isbel

Address

Department of Nephrology
Level 2 ARTS Building (31)
Princess Alexandra Hospital
199 Ipswich Road
Woolloongabba
QLD 4102

Country

Australia

Phone

+61 7 3240 2193

Fax

+61 7 3240 5245

Email

nikky_isbel@health.qld.gov.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.