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Trial registered on ANZCTR

Registration number

ACTRN12620000623998

Ethics application status

Approved

Date submitted

5/05/2020

Date registered

29/05/2020

Date last updated

29/05/2020

Date data sharing statement initially provided

29/05/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

Dietary Inulin for Gut Health in Solid-organ Transplantation (DIGEST)

Scientific title

An Investigator-Initiated, Randomized Controlled Trial Evaluating the Effect of High-Fibre Supplementation on Glycaemic Variability in Renal Transplant Recipients - A Pilot Study

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1247-6400

Trial acronym

DIGEST

Linked study record

Health condition

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

Kidney Transplant

New-Onset Diabetes Post-Transplant

Diabetes

Condition category

Condition code

Renal and Urogenital

Kidney disease

Diet and Nutrition

Other diet and nutrition disorders

Metabolic and Endocrine

Diabetes

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

100% Inulin Powder (MYPROTEIN)

Participants randomised to the intervention arm will be asked to supplement their diet with inulin for 4 weeks, commencing at day 28 post kidney transplant. Initially, participants will consume 10 grams of inulin in approximately 200mls of water each morning for one week, after which they will consume 10 grams morning and night for the remaining three weeks.

Inulin will be provided as a powder in individual dose sachets (10 grams) and is readily soluble in water. Participants will be asked to return their fibre supplement sachets for measurement at each study visit.

Participants will be asked to keep a 4-day food diary prior to and in the last 4 days of the fibre supplementation period.

Study visits will consist of 1 x 1-hour visit per week to monitor adherence and safety during the intervention period.

Intervention code [1]

Treatment: Other

Comparator / control treatment

Patients not randomised to receive inulin supplementation will continue with standard care and asked to consume approximately 200mls of water each morning for one week, following by 200mls of water morning and night for the remaining three weeks of the treatment period.

Standard care is defined as the usual post kidney transplant follow-up care in accordance with local policy and guidelines, at the discretion of the participants treating physician.

Control group

Active

Outcomes

Primary outcome [1]

To determine the feasibility of recruitment, randomisation, retention, and implementation of inulin supplementation in the early-post transplant period.

Timepoint [1]

Recruitment and eligibility rates will be determined at baseline. Retention rates will be determined at the conclusion of the study (at post-transplant week 12). Implementation will be assessed by the rate and percentage of eligible candidates recruited, by the percentage of participants completing all study visits, and by recorded adherence to the supplement. The feasibility of randomisation will be assessed by the number of enrolled participants who proceed to randomisation and complete the study period, determined at the conclusion of the study.

Primary outcome [2]

To determine the safety and tolerability of inulin supplementation in the early post-transplant period. Potential adverse reactions include changes in bowel frequency, cramping and bloating, and will be assessed using the Gastrointestinal Symptom Rating Scale (GSRS), and recording of all adverse events.
Adverse events will be recorded using Common Terminology Criteria for Adverse Events, adapted from the National Institute of Health (NIH Publication No. 09-5410)

Timepoint [2]

Measured just prior to the beginning of the supplementation period, on days 7 and 28 of the supplement, and at post-transplant week 12.

Secondary outcome [1]

Glycaemic control and variability as measured by 14-day continuous glucose monitoring - mean glucose, SD, CV%, average daily risk range (ADRR), mean amplitude of glycaemic excursion (MAGE), glycemic risk assessment diabetes equation (GRADE) score, time in range and above/below glycaemic thresholds, low blood glucose index & high blood glucose index (LGBI/HBGI)

Timepoint [1]

Commencing one week prior to the inulin supplementation period (post-transplant week 3), and one week prior to the cessation of inulin supplementation (post-transplant week 7)

Secondary outcome [2]

75-gram oral glucose tolerance test and glycosylated haemoglobin A1c (HbA1c)

Timepoint [2]

Post-transplant week 12, and month 12

Secondary outcome [3]

Cardiovascular risk profile (Fasting glucose, insulin, lipids, blood pressure, weight, and BMI)
Glucose, insulin, and lipid levels will be assessed by serum assay, and clinical parameters determined from manual sphygmomanometry and clinical examination as relevant.

Timepoint [3]

Measured within 1-7 days prior to commencement of the supplement, within 1-7 days prior to completing the supplement period, and at post-transplant week 12.

Secondary outcome [4]

Gut homeostasis (CRP, IL-6, IL-17, Zonulin, IgA, Lipopolysaccharides, leptin, adiponectin)
as measured by plasma/serum ELISA or chromogenic assay

Timepoint [4]

Measured within 1-7 days prior to commencement of the supplement, within 1-7 days prior to completing the supplement period, and at post-transplant week 12.

Secondary outcome [5]

Kidney allograft function - serum creatinine and estimated glomerular filtration rate (eGFR), and albuminuria determined by serum assay and urinalysis respectively

Timepoint [5]

Measured within 1-7 days prior to commencement of the supplement, within 1-7 days prior to completing the supplement period, and at post-transplant week 12.

Secondary outcome [6]

Gut microbiome will be assessed from bacterial DNA extracted from a stool sample.

Timepoint [6]

Measured within 1-7 days prior to commencement of the supplement, within 1-7 days prior to completing the supplement period, and at post-transplant week 12.

Secondary outcome [7]

Fasting serum levels of acetate

Timepoint [7]

Measured within 1-7 days prior to commencement of the supplement, within 1-7 days prior to completing the supplement period, and at post-transplant week 12.

Secondary outcome [8]

Habitual Diet

Timepoint [8]

Participants will be asked to keep 3 x 4-day food diaries to record their dietary intake, measured within 1-7 days prior to commencement of the supplement, within 1-7 days prior to completing the supplement period, and at post-transplant week 12.

Secondary outcome [9]

Biopsy proved acute allograft rejection and Donor Specific Antibodies (DSAs)

Timepoint [9]

To be assessed at any time of graft dysfunction at the discretion of the subjects treating physician, and at post-transplant week 12 as standard-care.

Secondary outcome [10]

Plasma immune cell populations

Timepoint [10]

Measured within 1-7 days prior to commencement of the supplement, within 1-7 days prior to completing the supplement period, and at post-transplant week 12.

Secondary outcome [11]

Hospitalisations

Timepoint [11]

Such an event will be reported to the trial/coordinator at any stage during the study, and patients will be assessed at each study visit, assessed for the duration of the study. This outcome will be assessed up to 12 weeks post-transplant.

Secondary outcome [12]

Infection, defined as the need for antimicrobial therapy and/or hospital admission

Timepoint [12]

Secondary outcome [13]

Insulin sensitivity - homeostatic model assessment/ insulin resistance (HOMA2/IR), fasting insulin levels, fasting blood glucose, and Matsuda Insulin Sensitivity Index (MSI).

Timepoint [13]

Measured within 1-7 days prior to commencement of the supplement, within 1-7 days prior to completing the supplement period, and at post-transplant week 12.

Eligibility

Key inclusion criteria

Recipients of a kidney transplant from a living or deceased donor, including patients who receive a kidney from an ABO blood group incompatible donor, or as part of the Paired Kidney Exchange Program
Individuals aged >= 18 years old who are able to give informed consent, and a willingness to participate and comply with the study requirements

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Individuals diagnosed with significant gastro-intestinal diseases e.g. inflammatory bowel disease, coeliac disease
Patients who receive anti-thymocyte globulin (ATG) as induction or treatment for rejection
Acute rejection in the first 4 weeks post-transplant
Delayed Graft Function requiring dialysis persisting beyond week 2 post-transplant
Presence of gastrointestinal tract output stoma
Current enrolment in another intervention or investigational drug trial
Recipients of multi-organ transplants (dual or en-bloc kidney transplants are not excluded)
Known food intolerance, allergy, or sensitivity to inulin or dietary fibre.
The inability or the unwillingness of individual or legal guardian to give written informed consent

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 will be concealed with central randomisation via computer (REDCap).

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomisation will occur centrally by permuted block randomisation using computer-generated numbers through the “blockrand” package for R, stratified by pre-transplant diabetic status to maintain balance between treatment arms. Random blocks will be generated in groups of 6 by the study co-investigator, and a randomisation list created and loaded to a central web-based randomisation module (REDCap).

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Our previous CGM data suggest n=20 per group will provide >80% power to detect a 50% reduction in post-transplant dysglycaemia, as defined by % time spent in hyperglycaemia. A larger study, informed by this pilot, will be required to determine the capacity of supplements to prevent new-onset diabetes after transplantation. For secondary end-point analyses, we will use Student t test or 1-way ANOVA for continuous data and Fisher’s exact test for categorical data. Mixed-effects linear regression will be used for comparison of glycaemic measures and pre-determined variables. DESeq2 analysis will be used to test for differential abundance of gut bacterial species. All statistical analyses will be performed using SPSS or R Studio.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

5/06/2020

Actual

Date of last participant enrolment

Anticipated

1/02/2021

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Royal Prince Alfred Hospital - Camperdown

Recruitment postcode(s) [1]

2050 - Camperdown

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Department of Renal Medicine, Royal Prince Alfred Hospital

Address [1]

Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
AUSTRALIA

Country [1]

Australia

Primary sponsor type

University

Name

University of Sydney

Address

Camperdown, Sydney
New South Wales 2006

Country

Australia

Secondary sponsor category [1]

Hospital

Name [1]

Royal Prince Alfred Hospital

Address [1]

Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
AUSTRALIA

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Human Research Ethics Committee (Royal Prince Alfred Hospital)

Ethics committee address [1]

Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

17/12/2019

Ethics approval number [1]

X19-0378 & 2019/ETH12932

Summary

Brief summary

Protocol: Kidney transplant recipients will be screened and enrolled at week 3 following transplantation. Participants will be randomised (1:1) to receive at 4 weeks post-transplant either inulin (intervention) or continue with standard care. Subjects randomised to receive inulin will be asked to drink 10g of inulin dissolved in 200ml water once daily for one week, and then twice daily for a further 3 weeks. Subjects randomised to standard care will be instructed to consume the same quantity of water, without additional supplementation. Compliance with fibre supplementation will be assessed by powder weight every 7 days. All participants will receive standard post-transplant care including immunosuppression and medication use will be recorded throughout the study. Participants will be asked to keep a 4-day food diary prior to and during the final 4 days of supplementation, to be analysed using Foodwerx. Subjects will undergo continuous glucose monitoring for 2 periods of 14 days, from week 3 and week 7 post-transplant, to measure insulin resistance (HOMA) and glycaemic control (mean glucose, time in diabetic range, GRADE and MAGE scores). Kidney function (eGFR, albuminuria) and allograft response (kidney biopsy and test for donor-specific antibodies) will be assessed at month 3 and at any time of graft dysfunction. Patients will provide blood and faecal samples for analysis of SCFA (serum and stool, by NMR spectroscopy) and microbiota/metagenome (stool, by 16s rRNA sequencing) at (1) pre-supplement; (2) last week of supplementation; (3) at month 3 post-transplant. Gut homeostasis (blood Zonulin, LPS, CRP, IL-6, IL-17) and symptoms (Gastrointestinal Ratings Scale), cardiovascular risk profile (lipids, blood pressure, weight, CVD events), infections and hospitalisations will be recorded.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Steven Chadban

Address

Kidney Node, Level 2
Charles Perkins Centre, Building D17
Johns Hopkins Drive (off Missenden Road)
The University of Sydney NSW 2006

Country

Australia

Phone

+61295156600

Fax

Steve.Chadban@health.nsw.gov.au

Contact person for public queries

Name

Julian Singer

Address

Kidney Node Laboratory, Level 5
Charles Perkins Centre, Building D17
Johns Hopkins Drive (off Missenden Road)
The University of Sydney NSW 2006

Country

Australia

Phone

+61 286277210

Fax

Julian.Singer@sydney.edu.au

Contact person for scientific queries

Name

Julian Singer

Address

Kidney Node Laboratory, Level 5
Charles Perkins Centre, Building D17
Johns Hopkins Drive (off Missenden Road)
The University of Sydney NSW 2006

Country

Australia

Phone

+61 286277210

Fax

Julian.Singer@sydney.edu.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?

Researchers requesting individual patient data will be considered on a case by case basis by the trial steering committee, all of the individual participant data collected during the trial, after de-identification, may be shared.

When will data be available (start and end dates)?

Data will be available 2 years following publication of the primary manuscript and available for a period of 15 years.

Available to whom?

Available to all researchers on a case by case basis. An independent review board will assess proposals based on the following criteria: sound science, benefit-risk balancing and research team expertise.

Available for what types of analyses?

Data analyses will be considered on a case by case basis

How or where can data be obtained?

An independent review board will assess proposals based on the following criteria: sound
science, benefit-risk balancing and research team expertise. Data sharing requests may be made by email to the Principal Investigator via email at steve.chadban@health.nsw.gov.au

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
6717	Study protocol			Julian.Singer@Sydney.edu.au

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Protocol for a pilot single-centre, parallel-arm, randomised controlled trial of dietary inulin to improve gut health in solid organ transplantation: The DIGEST study.	2021	https://dx.doi.org/10.1136/bmjopen-2021-049184

N.B. These documents automatically identified may not have been verified by the study sponsor.

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