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Trial registered on ANZCTR

Registration number

ACTRN12621001412820

Ethics application status

Approved

Date submitted

11/10/2021

Date registered

20/10/2021

Date last updated

20/10/2021

Date data sharing statement initially provided

20/10/2021

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 1: sirolimus-based immunosuppression

Scientific title

Rapamycin and Inulin for booster VAccine response STIMulation (RIVASTIM) - Part 1: The effect of rapamycin on booster COVID-19 vaccine responses in kidney transplant recipients

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1270-1439

Trial acronym

RIVASTIM

Linked study record

N/A

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

Normal development and function of the immune system

Inflammatory and Immune System

Other inflammatory or immune system disorders

Respiratory

Other respiratory disorders / diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Kidney transplant recipients receiving standard of care immunosuppression with tacrolimus, mycophenolate, and steroids, who are deemed to be non-responders or low-responders to conventional 2-dose COVID-19 vaccination, will be randomised to switch from mycophenolate to sirolimus. Participants will initially have mycophenolate ceased, and sirolimus tablets commenced at 2mg daily. The dose of sirolimus will be adjusted weekly to target trough levels of 3-6 ng/mL. Once sirolimus levels are therapeutic, tacrolimus dose will be adjusted to target trough levels of 3-5 ng/mL. Adherence will be monitored through weekly drug level monitoring. Four weeks after randomisation, participants will receive a 3rd COVID-19 mRNA vaccine dose (Pfizer Comirnaty). All participants will receive COVID vaccination during a clinical trial visit to ensure adherence. Participants will continue the altered immunosuppression regimen until measurement of vaccine responses at 4-6 weeks post vaccination. At that stage patients will be able to either continue the intervention immunosuppression or switch back to usual immunosuppression in conjunction with their treating nephrologist.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Active

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. Patients in the intervention group will also continue fortnightly immunosuppression level checks with phone call follow up for 6 weeks 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]

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 sirolimus switch as measured by proportion of patients ceasing study drug, patient-reported adherence, and incidence of drug-related adverse events including:
- new proteinuria (as measured by spot albumin:creatinine ratio)
- new anaemia
- new leukopaenia
- rash
- mouth ulcers
- pneumonitis

This information will be assessed at each clinical visit (phone or physical) by active questioning from the trial investigator. Patients will complete an EQ-5D questionnaire at each clinical visit. Investigations to monitor for the adverse events (blood tests, urine tests) will be conducted at baseline, at vaccination 4 weeks later, and at the concluding study visit 4-6 weeks post vaccination.

Timepoint [3]

During the 8-10 week clinical follow-up period following randomisation. Clinical visits for all patients will be at randomisation, vaccination 4 weeks later, follow up phone call 1 week post vaccination, and vaccination response assessment 4-6 weeks post vaccination.

Patients in the intervention arm will additionally have regular monitoring of immunosuppression levels, these will be assessed weekly during the first 4 weeks, and then fortnightly during the subsequent 4-6 weeks (or more frequently if indicated).

Secondary outcome [4]

Measurement of sirolimus effect on faecal microbiome as measured by DNA sequencing on faecal samples collected at randomisation and at vaccination

Timepoint [4]

Comparison between randomisation visit sample and vaccination visit sample at week 4

Eligibility

Key inclusion criteria

- Kidney transplant recipients
- Aged 18-70 years
- estimated GFR >25 mL/min
- Spot urinary albumin:creatinine ratio <100 mg/µmol
- Current immunosuppression regimen comprising tacrolimus, mycophenolate, prednisolone
- Treating nephrologist agrees that patient is suitable for sirolimus maintenance immunosuppression
- Have received 2 doses of a COVID-19 vaccine regimen (either adenoviral vector or mRNA-based) and have demonstrably not responded (anti-Receptor Binding Domain antibody titre < 100 U/mL)

Minimum age

18 Years

Maximum age

70 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- Multi-organ transplant recipients (e.g. kidney-pancreas)
- Aged <18 years or >70 years
- Significant kidney dysfunction, estimated GFR =25 mL/min or spot urinary albumin:creatinine ratio =100 mg/µmol
- Unable or unwilling to provide informed consent to participate in the trial
- Have received 2 doses of a COVID-19 vaccine regimen (either adenoviral vector or mRNA-based) and have mounted an adequate immune response (anti-Receptor Binding Domain antibodies >100 U/mL)
- Have had documented infection with COVID-19
- Known allergy to or intolerance of sirolimus or everolimus
- Patients who are currently pregnant

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 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 sirolimus intervention group, and 60 assigned to control. This will provide 80% statistical power (alpha 0.05) to detect an absolute difference of 25% in the proportion of patients who achieve the 22% neutralising antibody threshold necessary to provide clinical protection from COVID-19 disease, allowing for a 10% drop-out rate.

The primary outcome will be analysed as a dichotomous variable, considering the absolute proportion of patients achieving the target 22% 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]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [2]

The Royal Adelaide Hospital - Adelaide

Recruitment postcode(s) [1]

2050 - Camperdown

Recruitment postcode(s) [2]

5000 - Adelaide

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 transplant medication sirolimus shows promise in enhancing immune responses to COVID-19 vaccination. 

In this study kidney transplant patients receiving standard of care immunosuppression with tacrolimus, mycophenolate, and steroids will be randomised to either switch from mycophenolate to sirolimus, or remain on standard of care immunosuppression. 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 8 70740000

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
13504	Informed consent form					382891-(Uploaded-11-10-2021-14-36-02)-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 booster vaccine response stimulation (RIVASTIM)-rapamycin: study protocol for a randomised, controlled trial of immunosuppression modification with rapamycin to improve SARS-CoV-2 vaccine response in kidney transplant recipients.	2022	https://dx.doi.org/10.1186/s13063-022-06634-w

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

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