Trial design
This study is a single-centre, parallel group, double-blind, randomised placebo-controlled feasibility trial (Fig. 1). Informed consent will be obtained from all participants. The study will be conducted according to the International Committee of Harmonisation (ICH), Good Clinical Practice (GCP) guidelines and reported according to CONSORT guidelines. A SPIRIT checklist (Appendix 1) and schedule of enrolment, interventions, and assessments have been completed (Table 1).
Table 1. Schedule of enrolment, interventions and data collection.
Setting and participants
Sixty acute kidney transplant recipient patients will be recruited from the Princess Alexandra Hospital kidney transplant ward (Brisbane, Queensland, Australia) over a 6-month period. The Princess Alexandra Hospital is the only kidney transplant unit in Queensland and is the largest kidney transplant unit in the Oceania region. To be eligible to participate in this trial, participants must satisfy all of the following criteria: receive a kidney transplant at the Queensland Renal Transplant Service, be aged ≥ 18 years, and be able to provide informed consent. Patients will be excluded from participation if they meet any of the following criteria: have received radiation to the bowel and/or large bowel resection, medically diagnosed and active inflammatory bowel disease, unwilling or unable to meet the requirements of the protocol, and other medical, social, cultural, and/or linguistic reasons negatively affecting their adherence to the protocol, at the discretion of the investigators.
Participant identification and recruitment process
Patients will be provided with written and verbal information about the study while an inpatient in the transplant ward. They will be given the opportunity to ask questions, to take the information home with them when they leave hospital and to discuss it with friends, family, or others. They will be able to provide consent at one of their routine clinic visits in the early post-discharge period. This will ensure that the patients are physically and mentally well and stable, and thereby able to fully consider their participation in the study. Once they have consented to participate in the study (usually between day 5 to day 12 following acute kidney transplant), participants will commence the prebiotic powder or placebo suspended in water daily for four to six weeks. The initial dosage will be 7.5 grams daily for the first two weeks, thereafter increasing to 15 grams daily for the final two to four weeks of the study.
Treatment
This trial will consist of two arms; 1) Green Banana Resistant Starch (prebiotic supplement); 2) Waxy maize (matched, identical placebo).
Intervention – Green Banana Resistant Starch
The active intervention in this study will be Green Banana Resistant Starch Multi-Fibre. This is a functional food product structurally resistant to digestion in the small intestine19. When resistant starches reach the large intestine, the polymers can be deconstructed and fermented by the resident microbiota. The beneficial effects from these products include a laxative effect promoting regularity of bowel motions, and the capacity to promote the growth of select commensal microbes, in addition to beneficial effects reported on lipid-based biomarkers in subjects with type 2 diabetes mellitus.
Comparator – waxy maize
The comparator (control) in this study will be Waxy Maize, which is primarily comprised of branched starch polymers (amylopectin) that are more readily digestible in the small intestine. As such, much of the placebo should be digested proximal to the large intestine and will have limited impacts on the large intestinal microbiota.
Concomitant treatment
All other treatment, including medications, will be as per standard care for the patient.
Randomisation
Participants will be randomly assigned in a 1:1 ratio to receive either prebiotic or placebo. The randomisation schedule will be prepared by a researcher not involved with treatment allocation and will involve stratification factors of age (< 65years, ≥ 65 years) and sex. A blinded allocation list will be maintained in an Excel spreadsheet on a secure server not accessible to staff involved in study recruitment and data collection.
Blinding
Participants, caregivers, treating physicians and surgeons, laboratory staff and members of the study team will be blinded to the treatment. Only the statistician not involved with recruiting patients in this study will be aware of the product allocation sequence.
Primary and secondary outcomes
The primary outcome of this study is feasibility of recruitment which will be defined as at least 80% of eligible subjects recruited to the study.
The secondary outcomes will include;
a) Timeliness of recruitment
This will be assessed as the ability to successfully recruit 60 patients within six months.
b) Adherence
This will be assessed as the proportion of participants adherent to prescribed study therapy (intervention or placebo) over the period of the study. Adherence will be defined as having used 80% of more of the prescribed study therapy, calculated by the % of the expected weight of the product returned divided by the initial weight of study therapy.
c) Tolerance
This will be assessed as the proportion of patients who continue the prebiotic supplementation. Tolerance will be defined as 80% of the recruited patients taking the prescribed study therapy during the study period.
d) Gastrointestinal symptom assessment
The gastrointestinal symptom assessment will be assessed as the changes in the Gastrointestinal Symptom Rating Scale score from baseline compared with the score at the time of the completion of the PREBIOTIC trial.
e) Retention
This will be assessed as the proportion of patients who remain in the PREBIOTIC study for the entire study period.
f) Laboratory samples
There will be two aspects to this outcome. The first part will examine the proportion of participants providing two stool samples at designated times (during the first week and between four to six weeks post-kidney transplant) with sufficient material to assess gut microbiota (stool sample analysis via shotgun metagenomic sequencing to a target depth of 3Gbp using NovaSeq 6000, 2x150base pair, paired-end chemistry). The second part of this outcome will assess the proportion of participants providing two blood samples for serum indoxyl sulphate and p-cresyl sulphate measurement at designated times (during the first week and between week four to week six post-kidney transplant).
g) Quality of life
This will be assessed as the changes in the overall quality of life score (measured by EQ-5D survey) from baseline compared with the score measured at the completion of the PREBIOTIC trial.
h) Infectious events
This will be assessed as the proportion of patients who develop at least one infectious event requiring hospital admission or antimicrobial therapy. Infectious adverse events of special interest would include
-
Urinary tract infections
-
Gastrointestinal infections
-
Respiratory infections (e.g. community or hospital acquired)
-
Opportunistic infections (e.g. cytomegalovirus, BK virus)
-
Skin or soft tissue infections
-
Central nervous system infections
i) Safety
A serious adverse event (SAE) will be defined as any event/ reaction that results in death, is life-threatening, requiring hospitalisation or prolongation of exisiting hospitalisation, resulting in persistent or significant disability or incapacity. All SAEs will be documented and reported to the ethics committee for review.
Prebiotic supplementation may also increase serum potassium particularly during the early days following kidney transplantation. The hyperkalaemia may also be related to constipation from prebiotic supplementation. Nevertheless, the participant’s serum potassium will be checked as per usual clinical routine (daily for the first 3 weeks then thrice weekly thereafter). Patients may be advised to stop the prebiotic temporarily if their serum potassium levels increase above 6.0 mmol/L.
Data collection
Data will be entered into Microsoft Excel during the course of the feasibility study, and data will be recorded only by investigators of the study. This system will help ensure compliance with medical data privacy, security and Good Clinical Practice regulations. Data will be stored in password-protected files for fifteen years and then destroyed. Physical copies of data will be kept in a locked filing cabinet. The data to be collected in this study are depicted in Table 1.
Sample size
The sample size of 60 subjects to be randomised is based on the outcome of 80% of eligible patients being recruited and to allow 95% confidence intervals of between 67.5% and 90%.
Planned analysis
As this is a feasibility study, data will be analysed via descriptive statistics, expressing frequencies (percentages) for categorical data, mean ± standard deviation for continuous normally distributed data, or median [interquartile range] for continuous non-normally distributed data. In addition, confidence intervals will be presented for all descriptive statistics. Outcome measures and the corresponding statistical measures are shown in Table 2. Analysis will be performed on an intention-to-treat basis. Patients discontinuing the study drug for whatever reason will be encouraged to continue follow-up in the trial. The null hypothesis will be rejected at the 0.05 level. The statistical analyses will be performed using Stata (version 14, 2016, Statacorp, College Station, TX).
Table 2
Outcomes and corresponding measures.
Outcome
|
Measure
|
Proportion of eligible patients who agree to take part in the study
|
% (95% CI)
|
Ability to successfully recruit 60 patients within six months
|
% (95% CI)
|
Proportion of participants adherent to prescribed study therapy (intervention or placebo) over the period of the study.
|
% (95% CI)
|
Proportion of patients who continue to the prebiotic supplementation
|
% (95% CI)
|
Mean changes in the Gastrointestinal Symptom Rating Scale
|
Mean change (SD)
|
Proportion of patients who withdraw from the PREBIOTIC study
|
% (95% CI)
|
Proportion of participants providing two stool samples at designated times (the first week and between week four to week six post kidney transplant) to assess gut microbiota changes
|
% (95% CI)
|
Proportion of participants providing two blood samples at designated times (the first week and week six post kidney transplant)
|
% (95% CI)
|
Changes in the overall quality of life (measured by EQ-5D survey)
|
Mean change
(SD)
|
Proportion of patients with at least one infectious event
|
% (95% CI)
|
Ethical considerations
Ethical approval has been granted through the Metro South Human Research Ethics Committee (HREC/2020/QMS/51887) and The University of Queensland Human Research Ethics Committee (51887).
Trial governance
The Trial Management Group (TMG) comprising chief investigator and co-investigators will provide overall management of the study including clinical set-up and training, centre set-up in preparation for recruitment, promotion of the study and interpretation of the results.