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Trial registered on ANZCTR


Registration number
ACTRN12621001465842
Ethics application status
Approved
Date submitted
19/10/2021
Date registered
26/10/2021
Date last updated
26/10/2021
Date data sharing statement initially provided
26/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of sirolimus-based immunosuppression and dietary fibre supplementation on booster COVID-19 vaccine responses in kidney transplant recipients - Part 2: inulin dietary fibre supplementation
Scientific title
Rapamycin and Inulin for booster VAccine response STIMulation (RIVASTIM) - Part 2: The effect of inulin dietary fibre supplementation on booster COVID-19 vaccine responses in kidney transplant recipients
Secondary ID [1] 305538 0
Nil known
Universal Trial Number (UTN)
U111-1270-4262
Trial acronym
RIVASTIM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 323927 0
Drug-induced immunosuppression 323947 0
Vaccine non-response 323948 0
Condition category
Condition code
Infection 321440 321440 0 0
Other infectious diseases
Inflammatory and Immune System 321441 321441 0 0
Other inflammatory or immune system disorders
Inflammatory and Immune System 321465 321465 0 0
Normal development and function of the immune system
Respiratory 321466 321466 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Kidney transplant patients who are non- or low-responders to conventional 2-dose COVID-19 vaccination regimen will be randomised to receive 20g inulin daily, divided into 2 doses of 10g dissolved in 200mL water. For a week patients will take 10g daily in a single dose, uptitrating to 20g daily in 2 divided doses thereafter until the conclusion of the trial (8-10 weeks total therapy). Adherence will be monitored through return and weighing of unused supplement powder at conclusion of the trial. 4 weeks after randomisation patients will receive a 3rd COVID-19 mRNA vaccine (Pfizer Comirnaty) dose. All participants will receive COVID vaccination during a clinical trial visit to ensure adherence.
Intervention code [1] 321936 0
Treatment: Other
Comparator / control treatment
Kidney transplant patients who are non- or low-responders to conventional 2-dose COVID-19 vaccination regimen will be randomised to receive control 20g maltodextrin daily, divided into 2 doses of 10g dissolved in 200mL water. For a week patients will take 10g daily in a single dose, uptitrating to 20g daily in 2 divided doses thereafter until the conclusion of the trial (8-10 weeks total therapy). Adherence will be monitored through return and weighing of unused supplement powder at conclusion of the trial. 4 weeks after randomisation patients will receive a 3rd COVID-19 mRNA vaccine (Pfizer Comirnaty) dose. All participants will receive COVID vaccination during a clinical trial visit to ensure adherence.
Control group
Placebo

Outcomes
Primary outcome [1] 329224 0
Absolute proportion of patients in each arm meeting the threshold of 20.2% neutralising antibody required for clinical protection from SARS-CoV2 infection. Neutralising antibody titres will be assessed by dilution at which paCoV-2 live virus entry into angiotensin converting enzyme (ACE) 2 receptor positive cells by 50%.
Timepoint [1] 329224 0
4-6 weeks post-vaccination. During the intervening post-vaccination period patients will be clinically assessed once by phone 1 week post vaccination.
Secondary outcome [1] 402036 0
Quantification of T cell responses as measured by interferon gamma release assay (ELISPOT) to SARS-CoV2 viral peptides in each arm
Timepoint [1] 402036 0
4-6 weeks post-vaccination. During the intervening post-vaccination period patients will be clinically assessed once by phone 1 week post vaccination.
Secondary outcome [2] 402037 0
Capturing adverse events following immunisation (AEFI) including adverse events of special interest (AESI):
- Changes in kidney function (as measured by eGFR)
- 50% increase in proteinuria (as measured by spot urine albumin:creatinine ratio)
- Biopsy-proven acute rejection
- Recurrence of primary kidney disease. This will be assessed based on known primary kidney disease (prospectively collected information at enrolment using both patient history and electronic medical records) and either typical re-presentation of a known pathology (e.g. typical flare of IgA vasculitis) or transplant kidney biopsy.
- Patient reported experiences using the EQ-5D questionnaire
Timepoint [2] 402037 0
Incidence of AEFI will be captured during the 4 week period post-vaccination. This information will be collected using clinical assessment by phone 1 week following vaccination, and then again at the physical follow-up visit 4-6 weeks post-vaccination.
Secondary outcome [3] 402038 0
Safety and tolerability of inulin supplementation as measured by:
- Supplement cessation
- Supplement adherence
- Patient reported experiences using the Gastrointestinal Symptom Rating Scale (GSRS) at baseline, at vaccination, and at the end of the study period

This information will be assessed at each clinical visit (phone or physical) by active questioning from the trial investigator. Patients will complete a GSRS questionnaire at each physical clinical visit (baseline, vaccination, and 4-6 weeks later).
Timepoint [3] 402038 0
4-6 weeks post-vaccination. Data will be compared to baseline and vaccination timepoint. During the post-vaccination period patients will be clinically assessed once by phone 1 week post vaccination

Eligibility
Key inclusion criteria
Kidney transplant recipients
Aged 18-80 years
Have received 2 doses of a COVID-19 vaccine regimen (either adenoviral vector or mRNA-based) and have demonstrably not responded (undetectable anti-spike protein antibodies) or low response (anti-RBD antibody titre < 100 U/mL)
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Aged <18 years or >80 years
Multi-organ transplant recipients (e.g. kidney-pancreas)
Patients who are currently pregnant
Patient has an underlying condition predisposing to increased gut permeability (including, but not limited to: active or recent within 6 weeks gastrointestinal infection, inflammatory bowel disease, short-gut syndrome, or coeliac disease)
Have not received 2 doses of a COVID-19 vaccine regimen (either adenoviral vector or mRNA-based)
Have received 2 doses of a COVID-19 vaccine regimen (either adenoviral vector or mRNA-based) and have mounted an adequate immune response (anti-spike protein antibodies above detection threshold)

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. Central computerised randomisation will occur following enrolment using a centralised REDCaps database.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will occur via permuted blocked randomisation, stratified by site (RAH and RPA), time post vaccination, original vaccine type (AstraZeneca Vaxzevria or Pfizer Comirnaty) and antibody titre.
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
This study will enrol 120 patients, with 60 assigned to the dietary fibre supplementation intervention group, and 60 assigned to maltodextrose control. This is an exploratory pilot trial as there is inadequate data regarding inulin supplementation effect on vaccine responses to guide power calculations.

The primary outcome will be analysed as a dichotomous variable, considering the absolute proportion of patients achieving the target 20.2% neutralising antibody threshold in each group using the Wald statistic. A two-sample unpaired T test will also be conducted to compare total neutralising antibody levels between groups.

Secondary outcomes will be similarly analysed depending on whether they are categorical variables (comparison of proportions) or continuous variables (comparison of means).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/11/2021
Actual
Date of last participant enrolment
Anticipated
1/12/2021
Actual
Date of last data collection
Anticipated
1/03/2022
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA
Recruitment hospital [1] 20805 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 20806 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 35625 0
5000 - Adelaide
Recruitment postcode(s) [2] 35626 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 309905 0
Charities/Societies/Foundations
Name [1] 309905 0
Kidney, Transplant, Diabetes Research Australia
Country [1] 309905 0
Australia
Primary sponsor type
Individual
Name
Professor P. Toby H Coates (MBBS FRACP PhD)
Address
Director of Kidney and Islet Transplantation
Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE SA 5000
Country
Australia
Secondary sponsor category [1] 310936 0
None
Name [1] 310936 0
Address [1] 310936 0
Country [1] 310936 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309627 0
Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)
Ethics committee address [1] 309627 0
CALHN HREC Executive Officer
The Queen Elizabeth Hospital
Ground Floor, Basil Hetzel Institute
28 Woodville Road
WOODVILLE SOUTH SA 5011
Ethics committee country [1] 309627 0
Australia
Date submitted for ethics approval [1] 309627 0
08/10/2021
Approval date [1] 309627 0
13/10/2021
Ethics approval number [1] 309627 0
2021/HRE00354

Summary
Brief summary
The RIVASTIM trials aim to identify strategies to improve immunological responses to a 3rd booster dose of the mRNA Pfizer Comirnaty COVID-19 vaccine in a cohort of kidney transplant patients who have failed to achieve an adequate immune response to a standard two-dose COVID-19 vaccine course. Kidney transplant patients are a highly vulnerable group of immunosuppressed patients who suffer from disproportionately high COVID-19-related morbidity and mortality. The dietary fibre supplement inulin shows promise in enhancing immune responses to vaccination.

In this study kidney transplant patients will be randomised to either take inulin supplements or placebo. Four weeks after randomisation, participants will receive a 3rd COVID-19 vaccine dose, and immunological responses will be assessed 4-6 weeks later.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114822 0
Prof P Toby H Coates
Address 114822 0
Director of Kidney and Islet Transplantation
Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE 5000
Country 114822 0
Australia
Phone 114822 0
+61 08 7074 2516
Fax 114822 0
Email 114822 0
[email protected]
Contact person for public queries
Name 114823 0
Matthew Tunbridge
Address 114823 0
Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE 5000
Country 114823 0
Australia
Phone 114823 0
+61 08 7074 0000
Fax 114823 0
Email 114823 0
[email protected]
Contact person for scientific queries
Name 114824 0
Matthew Tunbridge
Address 114824 0
Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE 5000
Country 114824 0
Australia
Phone 114824 0
+61 08 7074 0000
Fax 114824 0
Email 114824 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?
Identifiable data will not be publicly released, however deidentified individual participant data including relevant demographic and health information, primary outcome (neutralising antibody), and secondary outcomes (other measures of immunological response, measures of vaccine safety/tolerability, measures of study medication safety/tolerability) will be made available as per below criteria.
When will data be available (start and end dates)?
3 months following publication of all study results. Data will no longer be available after 10 years.
Available to whom?
Applications from experienced investigators for trial data can be made through correspondence with the Principal Investigator (or the corresponding author in the case of published works)
Available for what types of analyses?
All reasonable requests from experienced investigators will be considered, including re-analysis of trial results, secondary outcomes analysis, and sub-group analysis
How or where can data be obtained?
After approval, deidentified data will be provided through access on a secure electronic platform. Approval can be sought through contacting the Principal Investigator by email ([email protected]), or the Corresponding Author for published data.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
13645Informed consent form    382941-(Uploaded-19-10-2021-23-29-43)-Study-related document.docx



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseRapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin - Study protocol for a pilot, multicentre, randomised, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients.2022https://dx.doi.org/10.1136/bmjopen-2022-062747
N.B. These documents automatically identified may not have been verified by the study sponsor.