Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000936022
Ethics application status
Not yet submitted
Date submitted
3/11/2010
Date registered
3/11/2010
Date last updated
3/11/2010
Type of registration
Prospectively registered

Titles & IDs
Public title
Vitamin D supplementation prior to surgery for colorectal cancer: a randomised pilot study.
Scientific title
Vitamin D supplementation prior to surgery for colorectal cancer.
Secondary ID [1] 252861 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colorectal Cancer 258393 0
Condition category
Condition code
Cancer 258564 258564 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Colorectal cancer patients scheduled to undergo routine elective surgery at Dunedin Hospital will be randomised to receive either a single oral 5mg dose of vitamin D3 (cholecalciferol), or identical placebo to be taken 7-21 days prior to surgery.

A dose of 5mg of vitamin D3 will consistently achieve therapeutic serum levels >80nmol/L, peaking at 1 week and gradually falling thereafter. The dose is safe and designed to rapidly achieve desirable levels without delaying surgery.

All patients enrolled will recieve all other treatment and care as they would have otherwise done so.
Intervention code [1] 257395 0
Treatment: Drugs
Comparator / control treatment
Oral microcellulose capsules identical in appearance to the Vitamin D3 capsules.
Control group
Placebo

Outcomes
Primary outcome [1] 259402 0
A significant increase in the expression of genes containing the Vitamin D responsive element (VDRE), in tumour tissue, in patients receiving active study medication compared to placebo.

Previously published data on the effects of vitamin D on gene expression in a colorectal cancer cell line will be used to identify genes that are responsive to vitamin D. Affymetrix microarray data from these experiments are available from the NCBI GEO database under the accession number GSE444. In addition, genes representing vitamin D targets in normal colon tissues will be identified by searching publically available colon array databases for expressed genes which contain the VDRE. The VDRE element is present within the promoter region of genes activated by vitamin D and therefore acts as a convenient tag to identify vitamin D responsive genes.

RNA will be isolated from CRC samples from 50 patients, half of whom will have received vitamin D. RNA expression profiles of the 50 tumour RNA samples will then be generated in the Otago Genomics Facility using Affymetrix HG-U133+2.0 GeneChips. Evidence of activation of vitamin D pathways in the tumours from treated and untreated patients will be determined using the vitamin D responsive genes identified above. This will be accomplished by generating a vitamin D meta-gene to represent the coordinated expression of these genes across all tumours, so that tumours exhibiting a molecular response to vitamin D will have high levels of the meta-gene. This meta-gene will then be tested for association with treatment status, as well as clinicopathological (e.g. tumour stage, histology etc), molecular (e.g. proliferation) and immune reponse variables.
Timepoint [1] 259402 0
Tissue samples will be collected on the day of surgery. These will be batched and analysed in the laboratory within 6 months of the final patients surgery.
Primary outcome [2] 259403 0
A significant difference between treatment groups with respect to macrophage activation against tumour tissue and their ability to prime T cells.

Macrophages isolated from the blood and tumour tissue of CRC patients will be infected with bacterial pathogens in vitro and their ability to destroy these agents measured by quantifying nitric oxide production using the Greiss reaction. Their ability to prime the adaptive immune response will also be measured by analysing activation of T cells recovered from patient tissues using flow cytometry of surface activation markers. Results will be compared between treatment and placebo groups.
Timepoint [2] 259403 0
Tissue samples will be collected on the day of surgery. These will be batched and analysed in the laboratory within 6 months of the final patients surgery.
Secondary outcome [1] 266196 0
Reduction in the incidence of post-operative infection.

Operative details, post-operative recovery and duration of hospitalisation will be recorded on the case report form, including infectious and other complications. These will be graded for severity according to the Dindo-Clavien classification.
Timepoint [1] 266196 0
Reviewed on the day of discharge from Dunedin Hosptial and at 1 month, 3 months and 6 months from date of surgery for each patient .

Eligibility
Key inclusion criteria
Patients with colon cancer as diagnosed by colonoscopy, CT or Barium enema scheduled for elective surgery at Dunedin Hospital.
Participant is willing and able to give informed consent for participation in the study.
Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Hypercalcaemia (> 2.6mmol/L).
Hypervitaminosis D.
Renal osteodystrophy with hyperphosphatemia.
Renal failure (requiring renal replacement therapy).
Sarcoidosis and possibly other granulomatous diseases.
Patients receiving treatment with thiazide diuretics.
Advanced liver disease (Childs-Pugh B or C).
Patients in whom there would be less than 7 days between randomisation and surgery.
Female participants who are pregnant, lactating or planning pregnancy during the course of the study.
Patients with rectal cancer due to difficulties obtaining fresh tissue without compromising histopathological examination.

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)
Patients will be identified at the time of colorectal cancer diagnosis based on a positive CT, colonoscopy or barium enema.

Patient notes will be reviewed to make a preliminary eligibility assessment. Patients who appear to be eligible will be contacted by telephone to discuss the study and ascertain willingness to participate.

Patients expressing an interest in study participation will be sent a patient information sheet for their review.

Patients will then be met to confirm eligibility, obtain informed consent and undergo testing of baseline plasma calcium and cholecalciferol. Where possible this visit will be arranged for the same day as other preoperative tests at Dunedin hospital. Where this is not possible then reasonable travel costs will be met by the investigator.

When baseline calcium has been determined as within normal limits then patients will be randomised to receive either a single oral dose of 2.5mg of vitamin D3 or identical appearing placebo.

Study drug will be dispensed to the patient 7 to 21 days prior to surgery together with instructions for self administration.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be undertaken by computerised random number generation with concealed treatment allocation using numbered containers. Participants and investigators will be blinded to treatment allocation until endpoints have been measured.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Bio-availability
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2011
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment outside Australia
Country [1] 2969 0
New Zealand
State/province [1] 2969 0
Otago

Funding & Sponsors
Funding source category [1] 257829 0
University
Name [1] 257829 0
University of Otago
Country [1] 257829 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
364 Leith Walk,
Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 257031 0
None
Name [1] 257031 0
Address [1] 257031 0
Country [1] 257031 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 259868 0
Lower South Regional Ethics Committee
Ethics committee address [1] 259868 0
c/- Ministry of Health
229 Moray Place
Dunedin
9016
Ethics committee country [1] 259868 0
New Zealand
Date submitted for ethics approval [1] 259868 0
19/11/2010
Approval date [1] 259868 0
Ethics approval number [1] 259868 0

Summary
Brief summary
Low levels of vitamin D have been linked to an increased risk of developing colorectal cancer, higher rates of cancer recurrence following surgery and reduced patient survival.

Previous studies have found that low Vitamin D levels are present in 50% of New Zealanders and 85% of bowel cancer patients at the time of diagnosis.

This study is a randomised double blind, placebo controlled trial in colorectal cancer patients.

Fifty patients will be randomised to receive a single dose of 100,000IU (2.5mg) of vitamin D or an identical placebo between 7 and 21 days prior to elective surgery.

Following surgery tumour and normal colon samples from the resected bowel will be collected to analyse the biological effects of vitamin D in these tissues.

If short duration preoperative exposure to vitamin D is to have an effect on colorectal cancer patients then vitamin D activity should be detectable in the tumour and colon tissue.

The activation of Vitamin D pathways in tumour cells will be determined by identification of RNA generated from transcription of Vitamin D responsive genes. Macropahges will be isolated from the blood and tumour tissue of CRC patients will be infected bacteria in the laboratory. Their ability to prime the immune system and destroy pathogens will be measured. Results will be compared between treatment and placebo groups.

Post-operative recovery will be recorded through ongoing review of patient notes, including infections and other complications graded by system and severity. Post-operative length of stay and details of post-operative adjuvant chemotherapy will be recorded. Clinico-pathological disease stage (TNM) will be captured through review of histology reports.

Long term follow up over a minimum 5 year period for recurrence and survival will occur, but this data will not be included in the primary analysis.

The study will provide new insight into how vitamin D supplementation affects tumour biology and inform future clinical studies aimed at improving patient outcome.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31765 0
Address 31765 0
Country 31765 0
Phone 31765 0
Fax 31765 0
Email 31765 0
Contact person for public queries
Name 15012 0
Professor John McCall
Address 15012 0
Department of Surgical Sciences,
4th Floor,
Dunedin Hospital,
201 Great King Street,
Dunedin 9016
Country 15012 0
New Zealand
Phone 15012 0
+64 3 474 7007 ext 8837
Fax 15012 0
Email 15012 0
john.mccall@otago.ac.nz
Contact person for scientific queries
Name 5940 0
Professor John McCall
Address 5940 0
Department of Surgical Sciences,
4th Floor,
Dunedin Hospital,
201 Great King Street,
Dunedin 9016
Country 5940 0
New Zealand
Phone 5940 0
+64 3 474 7007 ext 8837
Fax 5940 0
Email 5940 0
john.mccall@otago.ac.nz

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.