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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] 305472 0
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 323854 0
Drug-induced immunosuppression 323945 0
Vaccine non-response 323946 0
Condition category
Condition code
Infection 321363 321363 0 0
Other infectious diseases
Inflammatory and Immune System 321364 321364 0 0
Normal development and function of the immune system
Inflammatory and Immune System 321463 321463 0 0
Other inflammatory or immune system disorders
Respiratory 321464 321464 0 0
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] 321876 0
Treatment: Drugs
Comparator / control treatment
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 stay on the same immunosuppression regimen. Participants will receive a 3rd COVID-19 mRNA vaccine dose (Pfizer Comirnaty) 4 weeks after randomisation. All participants will receive COVID vaccination during a clinical trial visit to ensure adherence.
Control group
Active

Outcomes
Primary outcome [1] 329190 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] 329190 0
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] 401736 0
Quantification of T cell responses as measured by interferon gamma release assay (ELISPOT) to SARS-CoV2 viral peptides in each arm
Timepoint [1] 401736 0
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 [2] 401737 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] 401737 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] 401738 0
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] 401738 0
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] 401739 0
Measurement of sirolimus effect on faecal microbiome as measured by DNA sequencing on faecal samples collected at randomisation and at vaccination
Timepoint [4] 401739 0
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?
No
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] 20715 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 20716 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 35517 0
2050 - Camperdown
Recruitment postcode(s) [2] 35518 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 309828 0
Charities/Societies/Foundations
Name [1] 309828 0
Kidney, Transplant, Diabetes Research Australia
Country [1] 309828 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] 310863 0
None
Name [1] 310863 0
Address [1] 310863 0
Country [1] 310863 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309570 0
Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)
Ethics committee address [1] 309570 0
Ethics committee country [1] 309570 0
Australia
Date submitted for ethics approval [1] 309570 0
08/10/2021
Approval date [1] 309570 0
13/10/2021
Ethics approval number [1] 309570 0
2021/HRE00354

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114622 0
Prof P Toby H Coates
Address 114622 0
Director of Kidney and Islet Transplantation
Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE 5000
Country 114622 0
Australia
Phone 114622 0
+61 08 7074 2516
Fax 114622 0
Email 114622 0
[email protected]
Contact person for public queries
Name 114623 0
Matthew Tunbridge
Address 114623 0
Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE 5000
Country 114623 0
Australia
Phone 114623 0
+61 08 7074 0000
Fax 114623 0
Email 114623 0
[email protected]
Contact person for scientific queries
Name 114624 0
Matthew Tunbridge
Address 114624 0
Central and Northern Adelaide Renal and Transplantation Service
Royal Adelaide Hospital
Port Road ADELAIDE 5000
Country 114624 0
Australia
Phone 114624 0
+61 8 70740000
Fax 114624 0
Email 114624 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
13504Informed 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
SourceTitleYear of PublicationDOI
EmbaseRapamycin 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.2022https://dx.doi.org/10.1186/s13063-022-06634-w
N.B. These documents automatically identified may not have been verified by the study sponsor.