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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]

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

Drug-induced immunosuppression

Vaccine non-response

Condition category

Condition code

Infection

Other infectious diseases

Inflammatory and Immune System

Other inflammatory or immune system disorders

Inflammatory and Immune System

Normal development and function of the immune system

Respiratory

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]

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]

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]

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]

Quantification of T cell responses as measured by interferon gamma release assay (ELISPOT) to SARS-CoV2 viral peptides in each arm

Timepoint [1]

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]

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]

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]

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]

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?

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]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [2]

Royal Prince Alfred Hospital - Camperdown

Recruitment postcode(s) [1]

5000 - Adelaide

Recruitment postcode(s) [2]

2050 - Camperdown

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Kidney, Transplant, Diabetes Research Australia

Address [1]

Kidney, Transplant, Diabetes Research Australia
The Hospital Research Foundation Group Head Office
Level 1, 62 Woodville Road
Woodville, SA 5011

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)

Ethics committee address [1]

CALHN HREC Executive Officer
The Queen Elizabeth Hospital
Ground Floor, Basil Hetzel Institute
28 Woodville Road
WOODVILLE SOUTH SA 5011

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

08/10/2021

Approval date [1]

13/10/2021

Ethics approval number [1]

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

Prof P Toby H Coates

Address

Director of Kidney and Islet Transplantation
Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE 5000

Country

Australia

Phone

+61 08 7074 2516

Fax

Toby.Coates@sa.gov.au

Contact person for public queries

Name

Matthew Tunbridge

Address

Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE 5000

Country

Australia

Phone

+61 08 7074 0000

Fax

Matthew.Tunbridge@sa.gov.au

Contact person for scientific queries

Name

Matthew Tunbridge

Address

Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE 5000

Country

Australia

Phone

+61 08 7074 0000

Fax

Matthew.Tunbridge@sa.gov.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?

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 (toby.coates@sa.gov.au), or the Corresponding Author for published data.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
13645	Informed 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

Source	Title	Year of Publication	DOI
Embase	Rapamycin 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.	2022	https://dx.doi.org/10.1136/bmjopen-2022-062747

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

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