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Trial registered on ANZCTR


Registration number
ACTRN12612000804886
Ethics application status
Approved
Date submitted
14/10/2011
Date registered
1/08/2012
Date last updated
18/03/2019
Date data sharing statement initially provided
18/03/2019
Date results information initially provided
18/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The effects of butyrylated high amylose maize starch (Starplus B) on polyposis in familial adenomatous polyposis patients
Scientific title
A double blind, placebo controlled, randomised cross over trial to evaluate a novel and cost effective food supplement, butyrylated starch, on polyposis in familial adenomatous polyposis (FAP) patients.
Secondary ID [1] 273198 0
Nil
Universal Trial Number (UTN)
Trial acronym
AusFAP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Familial Adenomatous Polyposis 278971 0
Condition category
Condition code
Oral and Gastrointestinal 279147 279147 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will recruit participants with Familial Adenomatous Polyposis (FAP). The trial is a double blind, placebo controlled, randomised cross over trial to evaluate a novel and cost effective food supplement, butyrylated high amylose maize starch (HAMSB), compared to a control starch, low amylose maize starch (LAMS), on polyposis in FAP patients. The starches (20g dose size) will be ingested orally, twice per day, by way of combination with food for 6 months duration. The daily dose of HAMSB and LAMS is 40g/day.

Following a baseline colonoscopy/sigmoidoscopy and biopsy collection, participants will consume either HAMSB or placebo (LAMS) for 6 months (+/- 2 weeks) then undergo another colonoscopy/sigmoidoscopy examination and biopsy collection before crossing over to the alternate starch for 6 months. The second intervention period will be concluded with a colonoscopy/sigmoidoscopy with biopsies. Participants will then consume their normal diet for a further 6 months with no intervention and at the end of this period a final colonscopy/sigmoidoscopy and biopsy will be performed.
Intervention code [1] 269530 0
Treatment: Other
Comparator / control treatment
Low amylose maize starch (LAMS) 40g/day
Control group
Placebo

Outcomes
Primary outcome [1] 279777 0
Aim 1: Assess the efficacy of Starplus B at reducing polyp incidence
(i) In a defined area after appropriate clearance at sigmoidoscopy/colonoscopy, or
(ii) causing regression of small polyps left in situ in another defined area, and
(iii) in general throughout the large bowel
This will be done using colonoscopy/sigmoidoscopy procedures and video analysis.
Timepoint [1] 279777 0
Week 0, Week 26, Week 52, Week 78
Primary outcome [2] 279778 0
Aim 2: Determine the effect of Starplus B on molecular characteristics of typical polyps and on macroscopically normal adjacent rectal mucosa:
a. Measure rates of apoptosis in polyps and adjacent mucosa
b. Measure proliferation in polyps and adjacent mucosa
c. Measure surrogate markers of DNA damage in polyps and adjacent mucosa
Timepoint [2] 279778 0
Week 0, Week 26, Week 52, Week 78
Secondary outcome [1] 294408 0
Aim 2.1: Determine the proportion of esterified butyrate released in the gastrointestinal tract of FAP patients consuming Starplus B. This will be done by analysing faecal samples, using standard distillation procedures and gas chromatography, collected from 60 participants.
Timepoint [1] 294408 0
Week 0, Week 4, Week 26, Week 30, Week 52
Secondary outcome [2] 294409 0
Aim 2.2: Collect information on the normal diet of FAP patients, their baseline nutrient intake and the impact of supplementation on their diet. This will be done using a 24 hour diet recall.
Timepoint [2] 294409 0
Week 0, Week 12, Week 38
Secondary outcome [3] 294410 0
Aim 2.3: Determine the effects of consumption of Starplus B on gastrointestinal function and quality of life of FAP
patients. This will be done using a validated assessment tool for evaluating the quality of life and distress for gastrointestinal symptons (Eypasch et al., 1995 Gastrointestinal quality of life index: development, validation and application of a new instrument; British Journal of Surgery, 82, 216-222).
Timepoint [3] 294410 0
Week 0, Week 12, Week 26, Week 38, Week 52, Week 78

Eligibility
Key inclusion criteria
1. Medically diagnosed FAP with either an intact colon, or after colectomy with a residual ileorectal anastomosis (IRA) or ileal pouch
2. History of polyp detection at surveillance sigmoidoscopies or colonoscopies
3. Generally in good health
4. Available for the duration of the study
Minimum age
12 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Intolerant to high fibre products
2.Reported lactating, pregnant or wish to become pregnant during the study. If a participant becomes pregnant during the trial they will be withdrawn
3.Reported use of nonsteroidal anti-inflammatory drugs, aspirin or probiotics
4.Use of other medication or supplement that in the opinion of the gastroenterologist may interfere with polyp development or bowel or microbiota function for 2 months prior to and during the clinical intervention. Use of anti-diarrhoeal medication(s) is allowed as required
5.Use of antibiotics for 2 months prior to the commencement of the trial
6.Use of other experimental chemopreventative agents, including EPA, tumeric and curcumin for 6 months prior to and during the trial
7.Colonic or rectal surgery likely within 18 months.

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)
Randomisation is done centrally by an eCRF computer program which contains an algorithm that allocates the recruited participants to receiving either intervention or placebo starch in the first 6 months of the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation algorithm uses stratified allocation considering participants' age (3 categories available) and their surgery type (3 types possible).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
A detailed strategic review was undertaken by the AusFAP Management Committee in December 2015 to consider study issues. Statistical power was looked at closely to ensure the smaller than anticipated numbers of recruited participants was adequate for a publishable study. The original power calculations were based on advice provided by a statistician who estimated the study would require 120 participants (n=60/group). This was based on a power of 85%, effect size 20%, one-sided test, considering variance at one colonoscopy. As these calculations were based on a parallel study whereas the trial has a crossover design these original calculations over estimated the number of participants needed to complete the study.
A reviewing statistician recalculated the power calculation considering the differences in polyp number at colonoscopies 1 and 2. The calculations were based on the outcomes of a more recent publication (Ishikawa et al. Preventive effects of low-dose aspirin on colorectal adenoma growth in patients with familial adenomatous polyposis: double-blind, randomized clinical trial. Cancer Med. (2013) Feb;2(1):50-60). These investigators found a 23% difference between the number of participants with reduced polyps in the aspirin group compared to placebo group (n=17/group).
Using a conservative model independent of carryover or delayed effects based on differences in polyp number at colonoscopies 1 and 2 with a two-sided comparison (85% power, 23% difference in number of polyps) the number of participants required was estimated as 64 (n=32/group). A two sided comparison was considered more appropriate than a one sided test.
If there is no evidence of treatment carryover or delayed effects during review of the results a full crossover analysis using colonoscopies 1, 2 and 3 could be used. Under these circumstance the number of participants required to detect a significant difference in number of polyps would be 32 (n=16; using 85% power, 23% difference in polyp number)

Statistical Analysis Plan
The primary analysis will consider the impact of the starch on the incidence of new polyps at each colonoscopy. Three primary endpoints have been defined as:
1. The number of new polyps in the cleared tattooed area
2. The number of polyps showing partial or complete regression in the uncleared tattooed area
3. The change in the number of polyps in general throughout the large bowel
A separate analysis will be carried out for each of these endpoints to determine the size and statistical significance of the difference in incidence of new polyps between the Starplus B and placebo starch supplement diet periods.
These analyses will be undertaken using an appropriate mixed model with random effects to allow for repeated measures on individual participants. The distribution of polyp counts will be tested to select the appropriate distributional assumptions, and a normal or Poisson model fitted to the counts of new polyps, with correction for over-dispersion if necessary. A binomial model will be fitted to the counts of regressed polyps in the uncleared tattoo area. The effects of covariates, including age, surgery type, gender, hospital and food intake variables will be investigated and adjustments made for these variables if necessary.
Other endpoints will be analysed by similar methods. The GIQLI questionnaire results will be summarised using the standard approach (Clarke et al, 2011 based on Eypasch et al, 1995). If transformation to normality proves impossible, for example where there are numerous zero values, appropriate non-parametric tests will be used.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 10328 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 10329 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [3] 10330 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [4] 10331 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 10332 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 21997 0
3050 - Royal Melbourne Hospital
Recruitment postcode(s) [2] 21998 0
3144 - Malvern
Recruitment postcode(s) [3] 21999 0
3052 - Parkville
Recruitment postcode(s) [4] 22000 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 270032 0
Charities/Societies/Foundations
Name [1] 270032 0
Cancer Council NSW
Address [1] 270032 0
153 Dowling Street
Woolloomooloo NSW 2011
Country [1] 270032 0
Australia
Funding source category [2] 270033 0
Charities/Societies/Foundations
Name [2] 270033 0
Cancer Council QLD
Address [2] 270033 0
553 Gregory Terrace
Fortitude Valley Qld 4006
Country [2] 270033 0
Australia
Funding source category [3] 270034 0
Charities/Societies/Foundations
Name [3] 270034 0
Cancer Council VIC
Address [3] 270034 0
1 Rathdowne St
Carlton Vic 3053
Country [3] 270034 0
Australia
Funding source category [4] 270035 0
Charities/Societies/Foundations
Name [4] 270035 0
Cancer Council SA
Address [4] 270035 0
202 Greenhill Road
Eastwood SA 5063
Country [4] 270035 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
Grattan Street
Parkville Victoria 3050
Country
Australia
Secondary sponsor category [1] 269006 0
None
Name [1] 269006 0
Address [1] 269006 0
Country [1] 269006 0
Other collaborator category [1] 280006 0
Government body
Name [1] 280006 0
Commonwealth Scientific and Industrial Research Organisation (CSIRO) Food and Nutrition Flagship
Address [1] 280006 0
PO Box 10041
Adelaide BC SA 5000
Country [1] 280006 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 271988 0
Southern Health Human Research Ethics Committee B (EC00383)
Ethics committee address [1] 271988 0
Southern Health
Monash Medical Centre
246 Clayton Road
Clayton Victoria 3168
Ethics committee country [1] 271988 0
Australia
Date submitted for ethics approval [1] 271988 0
Approval date [1] 271988 0
31/08/2011
Ethics approval number [1] 271988 0
HREC/11/CHB/13
Ethics committee name [2] 287705 0
Royal Brisbane and Women's Hospital Human Research Ethics Committee (EC00172)
Ethics committee address [2] 287705 0
Royal Brisbane and Women's Hospital
Office of the Human Research Ethics Committee
Butterfield Street
Herston QLD 4029
Ethics committee country [2] 287705 0
Australia
Date submitted for ethics approval [2] 287705 0
Approval date [2] 287705 0
25/07/2012
Ethics approval number [2] 287705 0
HREC/11/QRBW/460
Ethics committee name [3] 287741 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [3] 287741 0
Research Office
Level 6, deLacey Building
St Vincent's Hospital
390 victoria Street
Darlinghurst Sydney NSW 2010
Ethics committee country [3] 287741 0
Australia
Date submitted for ethics approval [3] 287741 0
24/04/2012
Approval date [3] 287741 0
Ethics approval number [3] 287741 0
HREC/12/SVH/98

Summary
Brief summary
The aim of this clinical trial is to determine whether a novel starch (butyrylated high amylose maize starch, Starplus B) can protect against colorectal cancer. Butyrate is normally produced in the colon by the fermentation of dietary fibre, and Starplus B can increase the concentration of butyrate in the colon. Laboratory and animal experiments suggest butyrate from dietary Starplus B may reduce the risk of developing colon cancer.
The study is a double blind, randomised controlled trial involving 120 volunteers likely to develop a genetic form of colon cancer (familial adenomatosis polyposis, FAP). FAP patients usually have most of their colon surgically removed by their early 20’s, and require regular follow-up colonoscopies to ensure they do not develop tumours in their residual rectum. After a baseline colonoscopy the FAP volunteers consume either Starplus B or placebo starch for 6 months, and then undergo a colonoscopy to assess the number and size of polyps and to sample the lining of the colon for analysis. The volunteers then consume the other starch for 6 months, and undergo a further colonoscopy.
As the FAP gene mutation also occurs in the majority of sporadic (common) colorectal cancer, the study may identify a dietary chemo-preventative supplement which is likely to benefit the wider community who are at risk of developing sporadic colorectal cancer.
Trial website
Trial related presentations / publications
FA Macrae, A Boussioutas, B Flanders, JM Clarke, A Spigelman, M Appleyard, D Cameron, T Lockett. A potential chemopreventative food for Familial Adenomatous Polyposis: The AusFAP study (2017) 7th BIENNIAL meeting - International Society for Gastrointestinal Hereditary Tumors Incorporated, Florence Italy.

FA Macrae, A Boussioutas, JM Clarke, T Lockett. A potential chemopreventative food for familial adenomatous polyposis: The AusFAP Study (2014) Journal of Gastroenterology and Hepatology; 29 (Suppl. 2): 128

Poster presentation for pilot study related to clinical trial:
Julie Clarke, Alex Boussioutas, Trevor Lockett, Finlay Macrae. Will ingested esterified butyrate reduce polyposis in participants with familial adenomatous polyposis ? International Society for Gastrointestinal Hereditary Tumours (InSiGHT), Cairns Australia, 28-31 August 2013.
Public notes

Contacts
Principal investigator
Name 33261 0
Prof Finlay Macrae
Address 33261 0
Dept of Colorectal Medicine and Genetics Level 3 Centre, City Campus Royal Melbourne Hospital Grattan Street Parkville Victoria 3050
Country 33261 0
Australia
Phone 33261 0
+61 3 9342 7580
Fax 33261 0
+61 3 9348 2004
Email 33261 0
finlay.macrae@mh.org.au
Contact person for public queries
Name 16508 0
Prof Professor Finlay Macrae
Address 16508 0
Dept of Colorectal Medicine and Genetics
Level 3 Centre, City Campus
Royal Melbourne Hospital
Grattan Street
Parkville Victoria 3050
Country 16508 0
Australia
Phone 16508 0
+61 3 9342 7580
Fax 16508 0
+61 3 9348 2004
Email 16508 0
finlay.macrae@mh.org.au
Contact person for scientific queries
Name 7436 0
Dr Dr Julie Clarke
Address 7436 0
CSIRO Health and Biosecurity PO Box 10041 Adelaide SA 5000
Country 7436 0
Australia
Phone 7436 0
+61 8 8303 8925
Fax 7436 0
Email 7436 0
julie.clarke@csiro.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Undecided at this stage but likely de-identified individual participant data underlying published results only.
When will data be available (start and end dates)?
Access soon after publication of primary study manuscript.
The CSIRO Data Access Repository (DAP) is intended for long term storage of data, but this may be varied for individual projects.
Available to whom?
Requests for access to data for non-commercial purposes only will be considered on a case-by-case basis at the discretion of the project contact.
Available for what types of analyses?
At this stage available only to achieve the aims in the approved proposal and at the discretion of the project contact.
How or where can data be obtained?
Mediated access via project contact via CSIRO's Data Access Portal (data.csiro.au). Access is likely to require signing of data access or license agreement.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary