Trial Review

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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
13/10/2024
Date data sharing statement 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 recruited 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) were 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 consumed either HAMSB or placebo (LAMS) for 6 months (+/- 2 weeks) then under went another colonoscopy/sigmoidoscopy examination and biopsy collection before crossing over to the alternate starch for 6 months. The second intervention also concluded with a colonoscopy/ sigmoidoscopy with biopsies. Participants then consumed their normal diet for a further 6 months with no intervention and at the end of this period a final colonscopy/sigmoidoscopy and biopsy was 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
The primary outcome is the effect of HAMSB on global polyp number in the colon of participants with FAP.
Timepoint [1] 279777 0
Week 0, Week 26, Week 52, Week 78
Primary outcome [2] 279778 0
There can only be one primary outcome, which is described above
The sample analysis listed above will be undertaken as a separate study
Timepoint [2] 279778 0
Week 0, Week 26, Week 52, Week 78
Secondary outcome [1] 294408 0
Secondary endpoints included the number of small (<2.4 mm), medium (2.4-9 mm) and large (>9 mm) polyps in the large bowel and the total and number of small, medium and large polyps in tattoo areas 1 and 2.
Timepoint [1] 294408 0
Week 0, Week 4, Week 26, Week 30, Week 52
Secondary outcome [2] 294409 0
Exploratory endpoints included the intake of dietary fibre of FAP PTs, the gastrointestinal function and quality of life index (GIQLI) and the faecal SCFA concentrations of a sub-group of FAP PTs.
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
Secondary outcome [4] 440655 0
Safety endpoints include number and type of adverse events (AEs) and serious AEs (SAEs) experienced by PTs during the study.
Timepoint [4] 440655 0
Secondary outcome [5] 440656 0
Safety endpoints include number and type of adverse events (AEs) and serious AEs (SAEs) experienced by PTs during the study.
Timepoint [5] 440656 0
No longer required

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
Sex
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: analyses followed a prespecified statistical analysis plan (SAP)
The primary analysis considered the impact of the starch on the number and size of polyps at each colonoscopy. The outcomes were defined as:
1. Primary end point: the total number of polyps in the large bowel
2. Secondary outcomes;
a. The number and size of new polyps in the cleared tattooed area (tattoo 1)
b. The number and size of polyps left in situ in the uncleared tattooed area (tattoo 2)
A separate analysis was carried out for each of these endpoints to determine the size and statistical significance of the difference in incidence and size of polyps between the HAMSB and LAMS supplement diet periods.

Secondary endpoints included the number of small (<2.4 mm), medium (2.4-9 mm) and large (>9 mm) polyps in the large bowel and the total and number of small, medium and large polyps in tattoo areas 1 and 2. Exploratory endpoints included the intake of dietary fiber of FAP PTs, the gastrointestinal function and quality of life index (GIQLI) and the fecal SCFA concentrations of a sub-group of FAP PTs. Safety endpoints include number and type of adverse events (AEs) and serious AEs (SAEs) experienced by PTs during the study.

Generalized linear mixed effects models (GLMMs) suitable for count data (Poisson, negative binomial and zero-inflated Poisson) were used to estimate the effect of HAMSB on the primary and secondary outcomes. GLMMs takes into consideration missing data.
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.

The analysis of the intention-to-treat (ITT) population, which included all PTs who were randomised, was considered the primary analysis. A per-protocol (PP) analysis was also performed, consisting of all study PTs who were randomized, achieved >50% treatment compliance, and did not experience major protocol violations.

Analyses were conducted using Stata/SE for Windows version 17 (64-bit x86-64) or higher, or R software version 4.3.1 or higher. Count regression modelling was performed using R’s glmmTMB package (Brooks ME, et al. glmmTMB Balances Speed and Flexibility Among Packages for Zero-inflated Generalized Linear Mixed Modeling. R Journal. 2017; 9: 378-400.).

Linear mixed effects models were used to estimate the difference between mean nutrient intakes of fiber and calcium, and total GIQLI scores for HAMSB compared to LAMS. These included time (baseline, weeks 12, 26, 38, 52 and 78), treatment, stratification factors (age and surgery type), and a random individual effect to account for the correlation between total GIQLI scores from the same individual.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/12/2012
Actual
9/01/2014
Date of last participant enrolment
Anticipated
Actual
17/11/2016
Date of last data collection
Anticipated
7/05/2018
Actual
7/05/2018
Sample size
Target
64
Accrual to date
Final
49
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
Country [1] 270032 0
Australia
Funding source category [2] 270033 0
Charities/Societies/Foundations
Name [2] 270033 0
Cancer Council QLD
Country [2] 270033 0
Australia
Funding source category [3] 270034 0
Charities/Societies/Foundations
Name [3] 270034 0
Cancer Council VIC
Country [3] 270034 0
Australia
Funding source category [4] 270035 0
Charities/Societies/Foundations
Name [4] 270035 0
Cancer Council SA
Country [4] 270035 0
Australia
Funding source category [5] 317623 0
Hospital
Name [5] 317623 0
Royal Melbourne Hospital
Country [5] 317623 0
Australia
Funding source category [6] 317624 0
Other
Name [6] 317624 0
CSIRO Health and Biosecurity
Country [6] 317624 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) Health and Biosecurity
Address [1] 280006 0
PO Box 10041
Adelaide BC SA 5000
Country [1] 280006 0
Australia
Other collaborator category [2] 283253 0
Hospital
Name [2] 283253 0
Royal Brisbane and Women's Hospital
Address [2] 283253 0
Country [2] 283253 0
Australia
Other collaborator category [3] 283254 0
Government body
Name [3] 283254 0
St Vincent's Hospital, Sydney
Address [3] 283254 0
Country [3] 283254 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
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
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
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
Trial website
Trial related presentations / publications
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
[email protected]
Contact person for public queries
Name 16508 0
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
[email protected]
Contact person for scientific queries
Name 7436 0
Professor Finlay Macrae
Address 7436 0
Dept of Colorectal Medicine and Genetics Level 3 Centre, City Campus Royal Melbourne Hospital Grattan Street Parkville Victoria 3050
Country 7436 0
Australia
Phone 7436 0
+61 3 9342 7580
Fax 7436 0
Email 7436 0
[email protected]

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 Professor Finlay Macrae. Access is likely to require signing of data access or license agreement.


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
SourceTitleYear of PublicationDOI
EmbaseCan butyrate prevent colon cancer? The AusFAP study: A randomised, crossover clinical trial.2023https://dx.doi.org/10.1016/j.conctc.2023.101092
N.B. These documents automatically identified may not have been verified by the study sponsor.