Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001527853
Ethics application status
Approved
Date submitted
24/09/2021
Date registered
10/11/2021
Date last updated
9/11/2022
Date data sharing statement initially provided
10/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Specialised Dietary Fibre Intervention in Children with Type 1 Diabetes
Scientific title
Specialised Dietary Fibre Intervention in Children with Type 1 Diabetes - is it safe, feasible and tolerable?
Secondary ID [1] 304342 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 diabetes 322673 0
Condition category
Condition code
Metabolic and Endocrine 320289 320289 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tapioca-based type 4 resistant starch
- resistant starch and butyrate are the only active ingredients in this fibre supplement.
This is a colourless, tasteless, odourless powder that will be added to participants' usual diet for 6 weeks. It can be mixed with hot/cold food or drinks, dissolving easily without any effect on the starch structure. A dietitian will provide participants with information on how to incorporate the fibre supplement into their usual daily diet. The fibre supplement will be transferred from its original packaging into blinded and coded containers each containing a sufficient amount of fibre supplement for one participant for 6 weeks. The labelling of these containers will be generic and not indicate the nature of the supplement.

Dosing of the fibre supplement will be weight-based
- participants < 25kg will take 10g/day (2 x 5g doses/day)
- participants 25 - 50kg will take 20g/day (2 x 10g doses/day)
- participants > 50kg will take 40g/day (2 x 20g doses/day)
To improve tolerability, participants will start on 25% of the the total dose, increasing to 50%, 75% and then 100% (full dose) in two-day intervals. If a dose increase isn't tolerated, the participant will remain on the previous dose for two more days before trying to increase the dose again. If after three attempts the dose increase isn't tolerated, they will remain on the highest tolerated dose for the remainder of the 6 weeks.

Participants will keep a log book of what doses of supplement they take each day during the 6 weeks and will be asked to return any leftover fibre supplement at the end of the 6 weeks. They will also have weekly phone reviews during the 6 weeks they are taking the fibre supplement to administer a supplement survey and monitor for issues.
Intervention code [1] 321066 0
Treatment: Other
Comparator / control treatment
Maize-based type 2 resistant starch
- resistant starch is the only active ingredient in this fibre supplement

The type of starch provided is the only difference in procedures between the control/intervention groups
Control group
Active

Outcomes
Primary outcome [1] 328142 0
Is the tapioca-based type 4 resistant starch (dietary fibre supplement) tolerable in children and adolescents with type 1 diabetes (composite outcome)

Information will be gathered from participants logbooks, supplement survey results, quality of life questionnaires (gastrointestinal symptoms and diabetes modules), participant feedback, and from an audit of study records, to answer the following questions
- Dose tolerability: How many subjects could not tolerate the full dose? What proportion of subjects remained at each lower dose level? How many attempts did it take participants to move up to each dose level? What were the primary reasons for remaining at a lower dose?
- Participant feedback: Did the participants report satisfaction with the taste, smell and texture of the supplement? Did they have any difficulty incorporating the supplement into their diet? Did they report any barriers to completion of the required dose regimen?
Timepoint [1] 328142 0
At completion of 6 weeks of dietary fibre intervention
Primary outcome [2] 329268 0
Is the tapioca-based type 4 resistant starch (dietary fibre supplement) safe in children and adolescents with type 1 diabetes (composite outcome)

Information will be gathered from participants blood tests and logbooks, blinded CGM data, supplement survey results, quality of life questionnaires (gastrointestinal symptoms and diabetes modules), anthropometric data, and from an audit of study records, to answer the following questions
- Toxicity: Were any measurements outside of the normal expected ranges? Did any changes in toxicity measures correlate with supplement dose or time on supplement?
- Glycaemic control: Were there any changes in the frequency, duration or severity of hypo- or hyperglycaemia events or in glycaemic variability at any timepoint compared to baseline?
- Growth: Was there any weight loss or negative impact on growth at any timepoint compared to baseline?
Incidence of adverse events: What was the frequency of adverse events and unexpected suspected adverse reactions? What type of adverse events occurred? Were any of these events serious? Was there any relationship to timing of starting the supplement or dose?
Timepoint [2] 329268 0
At completion of the 6 weeks of dietary fibre intervention
Primary outcome [3] 329269 0
Is the tapioca-based type 4 resistant starch (dietary fibre supplement) feasible in children and adolescents with type 1 diabetes (composite outcome)

Information will be gathered from participants blood and stool tests, logbooks, supplement survey results, quality of life questionnaires (gastrointestinal symptoms and diabetes modules), and from an audit of study records, to answer the following questions
- Compliance: What proportion of supplement was returned unused? What proportion of doses were recorded as consumed? Did stool SCFA measurements reflect self-reported compliance?
- Withdrawal rate: How many participants withdrew 1) altogether, 2) primarily due to the supplement, 3) due to other aspects of the trial design, 4) for reasons unrelated to the trial?
- Data Completion and accuracy: What proportion of essential study data was completed? What were the major barriers to completion?
Timepoint [3] 329269 0
At completion of the 6 weeks of dietary fibre intervention
Secondary outcome [1] 397815 0
Exploratory outcome - short chain fatty acid analysis

Blood and stool samples collected at baseline (week 0), completion of the 6 weeks of dietary fibre intervention (week 6) and at completion of the 12 weeks of the study (week 12) will be processed for short chain fatty acid analysis using gas chromatography (GC-MS), with a focus on butyrate levels
Timepoint [1] 397815 0
At completion of 6 weeks of dietary fibre intervention and at completion of the 12 weeks of the study
Secondary outcome [2] 401965 0
Exploratory composite outcome - immune cell phenotype

From blood samples collected at week 0, week 6 and week 12, PBMC aliquots will be stored for later analysis for mass flow cytometry (CyTOF) analysis of immune cell phenotypes. A 47- marker panel assessing the major immune cell populations (T-cell subsets [CD4, CD8, regulatory, naïve, memory, effector, B-cell subsets [naïve, memory, effector, mature plasma B cells, monocytes], dendritic cells) along with an activation and exhaustion markers. Changes compared to baseline include ratios of regulatory to effector cell populations, antigen presenting cells etc. using viSNE.
Timepoint [2] 401965 0
At completion of 6 weeks of dietary fibre intervention and at completion of the 12 weeks of the study
Secondary outcome [3] 401966 0
Exploratory outcome - gut microbiome analysis

Stool samples collected at week 0, week 6 and week 12 will be stored for later DNA extraction for microbiome (metagenomic) sequencing analysis to be performed using a NovaSeq platform to a depth of 8-10Gbp data per sample. Metagenomics will assess abundance of bacterial species, providing a global assessment of intestinal function, health or inflammation, bacterial function and exocrine pancreatic output
Timepoint [3] 401966 0
At completion of 6 weeks of dietary fibre intervention and at completion of the 12 weeks of the study
Secondary outcome [4] 401976 0
Exploratory outcome - Quality of life
Did taking the dietary fibre supplement impact on participants quality of life at any timepoint compared to baseline?

Participants will complete age-specific, validated quality of life questionnaires (PedsQL gastrointestinal symptoms module and diabetes module) at week 0, week 6 and week 12 to see if there are any differences in their quality of life scores pre, immediately post, and 6 weeks post intervention
Timepoint [4] 401976 0
At completion of 6 weeks of dietary fibre intervention and at completion of the 12 weeks of the study

Eligibility
Key inclusion criteria
- Children and adolescents aged 5 – 14 years (inclusive) with T1D that was diagnosed at least 3 months prior to entry into the study
- HbA1c less than or equal to 9% (75 mmol/mol) at the time of entry into the study
- BMI between 15th centile and 85th centile, inclusive
- The child/adolescent and their family are willing and able to follow the study protocol
Minimum age
5 Years
Maximum age
14 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Concomitant disease or treatment that may, in the judgement of the investigators, impact on glycaemic control, insulin requirements or other outcome measures
- Hypoglycaemia unawareness
- History or symptoms of malabsorption or gastrointestinal disease, including coeliac disease
- Known liver or renal disease
- On a restricted or special diet that would impact their ability to take the supplement e.g. intermittent fasting or ketogenic diet
- Use of medication other than insulin that affects glucose homeostasis
- Antibiotic usage within the six weeks prior to entry into the study or anticipated usage during the study

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)
Allocation concealment achieved by
- study team members involved in recruitment and enrolment of participants, and overall running of the study, not being involved in the randomisation process
- allocation will involve contacting the holder of the allocation schedule who is "off site" and will allocate participants to intervention or control groups using this schedule. The labelling of the fibre supplement given to participants will be generic and not indicate its nature
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation.
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size + statistical power
- In the adult study, 21 subjects were recruited, 3 withdrew, 17 subjects completed the study on the full dose and 1 subject completed on a half dose of fibre. A power calculation was performed based on the butyrate concentration in plasma at baseline in the adult study (26.3+/-18.8 uM). With 11 children per group, we would have 80% power (alpha 0.05) to detect a two-fold increase in plasma butyrate.
- We will use n=15 per group. Participants will continue to be recruited until we have 30 (15 in each group) that have completed the study. We therefore anticipate recruiting a maximum of 40 – 50 participants, which will allow for a drop-out rate of up to 40%.

Statistical Methods
- We will use generalised estimating equation linear models to compare changes in plasma and faecal SCFAs, glycaemic control and dietary variables over time and between groups. Co-variates such as age, sex and disease duration will be investigated and adjusted for in the models. Correlations between SCFA concentrations, diet and glycaemic control will be investigated accounting for repeated measures.
- Given a disease protective type 4 resistant starch supplement in mice induced an expansion of total B cells and after 6-weeks of wash out period and butyrate is known to expand regulatory T cells, we will specifically look for correlations between Treg function with clinical tolerance induction. We hypothesise this may be predictive of the efficacy of the intervention.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
13/12/2021
Actual
10/10/2022
Date of last participant enrolment
Anticipated
28/04/2023
Actual
Date of last data collection
Anticipated
4/08/2023
Actual
Sample size
Target
30
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 20174 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 34904 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 308714 0
Other
Name [1] 308714 0
Australasian Paediatric Endocrinology Group (APEG) Research Industry Grant
Country [1] 308714 0
Australia
Funding source category [2] 309380 0
Charities/Societies/Foundations
Name [2] 309380 0
The Helpful Foundation
Country [2] 309380 0
Australia
Primary sponsor type
Hospital
Name
Queensland Children's Hospital
Address
Paediatric Endocrinology Department
Queensland Children's Hospital
501 Stanley Street
South Brisbane QLD 4101
Country
Australia
Secondary sponsor category [1] 310353 0
None
Name [1] 310353 0
Address [1] 310353 0
Country [1] 310353 0
Other collaborator category [1] 281933 0
University
Name [1] 281933 0
University of Queensland
Address [1] 281933 0
Translational Research Institute
University of Queensland
37 Kent St
Woolloongabba QLD 4102
Australia
Country [1] 281933 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308639 0
Children's Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 308639 0
Level 7, Centre for Children's Health Research
Queensland Children's Hospital Precinct
62 Graham Street, South Brisbane, QLD 4101
Ethics committee country [1] 308639 0
Australia
Date submitted for ethics approval [1] 308639 0
01/03/2021
Approval date [1] 308639 0
10/05/2021
Ethics approval number [1] 308639 0
HREC/21/QCHQ/73577

Summary
Brief summary
This is a 12-week double-blinded randomized control trial designed to assess the safety, feasibility and tolerability of a specialised dietary fibre supplement targeting the gut microbiota in children with type 1 diabetes (T1D); and to explore what impact it has on glycaemic control. Previous research has shown this dietary fibre supplement, which is a tapioca-based type-4 resistant starch that can be added to a normal diet, modifies the gut microbiota and promotes release of large amounts of the short chain fatty acids (SCFAs) after fermentation in the colon. In mice, the increase in SCFAs acetate and butyrate stopped pancreatic beta-cell damage providing near-complete protection from T1D. Studies in healthy human adults have shown this tapioca-based type 4 resistant starch supplement was well tolerated and improved glycaemic profiles through a reduction in post-prandial glucose and insulin excursions.

In this study, children aged 5 – 14 years with T1D for at least 3 months, an HbA1c <9%, and BMI between 15th and 85th centile will be randomized to the intervention (tapioca-based type 4 resistant starch) or control (maize-based type 2 resistant starch) group. They will take this dietary fibre supplement daily for six weeks as part of their usual diet then return to their usual diet (without the dietary fibre supplement) for the final six weeks. They will be monitored throughout the study via in-person and phone reviews, with various measures including blood and stool samples, quality of life (QoL) questionnaires, supplement tolerability surveys, food diaries, continuous glucose monitoring (CGM), insulin dose reviews and growth parameters.

The hypothesis is that inclusion of this tapioca-based type 4 resistant starch dietary fibre supplement into the normal diet of children with T1D will be safe, feasible and well tolerated; and it will also have a positive impact on their glycaemic control. It is hoped this study will provide important preliminary data for a Phase II study looking at efficacy of this supplement for preservation of beta-cell function and improving glucose homeostasis in children with newly diagnosed T1D.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111394 0
Dr Dana Signal
Address 111394 0
Paediatric Endocrinology Department
Queensland Children's Hospital
501 Stanley Street, South Brisbane QLD 4101
Country 111394 0
Australia
Phone 111394 0
+61 07 30681111
Fax 111394 0
Email 111394 0
dana.signal@health.qld.gov.au
Contact person for public queries
Name 111395 0
Dana Signal
Address 111395 0
Paediatric Endocrinology Department
Queensland Children's Hospital
501 Stanley Street, South Brisbane QLD 4101
Country 111395 0
Australia
Phone 111395 0
+61 07 30681111
Fax 111395 0
Email 111395 0
dana.signal@health.qld.gov.au
Contact person for scientific queries
Name 111396 0
Dana Signal
Address 111396 0
Paediatric Endocrinology Department
Queensland Children's Hospital
501 Stanley Street, South Brisbane QLD 4101
Country 111396 0
Australia
Phone 111396 0
+61 07 30681111
Fax 111396 0
Email 111396 0
dana.signal@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data not publicly available for privacy reasons


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.