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Trial registered on ANZCTR


Registration number
ACTRN12621000523808
Ethics application status
Approved
Date submitted
6/11/2020
Date registered
4/05/2021
Date last updated
4/05/2021
Date data sharing statement initially provided
4/05/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
The REPLACE study - renal transplant of HCV RNA positive donor kidneys into HCV RNA negative recipients: a pilot study
Scientific title
The REPLACE study - an investigator-initiated pilot study to determine the safety and efficacy of transplanting HCV-positive donor kidneys into HCV-negative recipients.
Secondary ID [1] 303884 0
nil known
Universal Trial Number (UTN)
Trial acronym
REPLACE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
end stage renal failure 319652 0
renal transplant 319653 0
Condition category
Condition code
Renal and Urogenital 317584 317584 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be eligible for this study if they are being wait-listed for renal transplant as part of standard practice and according to national guidelines for renal transplantation.

Patients identified as eligible (and on a wait list for renal transplant) will be considered for the study. Patients (potential recipients) who consent will be screened for Hepatitis C (HCV) infection by a serum HCV RNA PCR test (standard test) to exclude active hepatitis C infection prior to transplant.

HCV RNA positive-kidneys will be identified as part of the routine organ donor screening process (NAT testing for HCV RNA). When a HCV RNA positive donor organ becomes available, the enrolled patient will be offered that kidney, If they accept, renal transplant will occur as per standard practice. Following transplant, patients will be tested for serum HCV RNA at day 7 and if patient becomes HCV viremic, they will be commenced on anti-HCV treatment (glecaprevir (300mg daily plus pibrentasvir 120mg daily, taken orally) for 12 weeks.


Patients who test negative for HCV RNA at day 7 post-transplant will be re-tested at day 28 and then at week 8 and week 12 to confirm that they remain HCV RNA negative. If they become HCV RNA positive at day 28 / week 8 or week 12 they will progress to antiviral treatment.

Adherence will be monitored closely as part of the protocol, and by the renal physicians looking after these patients (clinical review multiple times per week is standard for the first 3-6 months post renal transplant) - these will take the form of regular verbal reminder and reinforcement at each clinical review, as is standard for anti-rejection medication. HCV RNA will be monitored during treatment, as suppression of serum HCV RNA levels is an indicator of adherence and treatment response.

Intervention code [1] 319005 0
Treatment: Drugs
Intervention code [2] 319719 0
Treatment: Other
Comparator / control treatment
n/a
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325628 0
Primary Endpoint
- Sustained virologic response (SVR), defined by undetectable serum HCVRNA levels 12 weeks post-treatment (SVR12).
Timepoint [1] 325628 0
12 week post commencement of anti-HCV treatment.
Secondary outcome [1] 388598 0
rate of acute HCV infection, measured by detectable HCVRNA in plasma samples post transplant
Timepoint [1] 388598 0
baseline, week 1, week 12 (end of treatment), week 4, 12, 24 post end of treatment.
Secondary outcome [2] 392241 0
rate of clinical symptoms attributable to acute HCV, as measured by clinician review
Timepoint [2] 392241 0
daily clinical review following transplant
Secondary outcome [3] 393772 0
rate of ALT rise in renal transplant recipient.
Timepoint [3] 393772 0
blood test as per protocol (Visit 2, 3, 4 and 5; post HCV treatment Week 4, 12 and 24), and as clinically indicated
Secondary outcome [4] 393774 0
Rate of delayed graft function in renal transplant recipient.
Timepoint [4] 393774 0
blood test (renal function) as per protocol - Visits 2, 3, 4 and 5 and post HCV treatment Week 4, 12 and 24.
Secondary outcome [5] 393776 0
rate of acute rejection episodes in renal transplant recipient. Episodes of acute rejection will be reported by the local investigator according to accepted standard of care of the centre. episodes will be reported using the protocol's e-clinical report forms.
Timepoint [5] 393776 0
total number of episodes counted in total number of transplant recipients at end of study.
Secondary outcome [6] 393777 0
Rate of dose adjustment of immunosuppressive medication. Dose of immunosuppressive (anti-rejection) medication will be reported by the local investigator using the protocol's e-clinical report forms.
Timepoint [6] 393777 0
at final analysis, at end of study.
Secondary outcome [7] 393778 0
number of serious adverse events attributable to HCV therapy in post-renal transplant recipients, including clinically significant drug-drug interactions. serious adverse events will include all episodes that require hospitalisation, as well as al episodes of acute organ rejection requiring treatment. Adverse events will be reported by the local investigator using the protocol's e-clinical report forms.
Timepoint [7] 393778 0
final analysis at end of study.

Eligibility
Key inclusion criteria
Inclusion criteria – recipient:
Age 40-70 years
On chronic haemodialysis or peritoneal dialysis
Listed for an isolated kidney transplant
No available living kidney donor
Blood group A, B, or O
Obtained agreement for participation from the patient's treating transplant nephrologist No evident contraindication to renal transplantation
No active illicit substance abuse
Weight at least 50kg
Able to provide informed consent

Inclusion criteria – donor organ:
Detectable HCV RNA by NAT testing
Age 18 to 65 years
Minimum age
40 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria - recipient:
- Hepatocellular carcinoma
- Patients with a history of primary focal segmental glomerulosclerosis (FSGS), FSGS recurring after previous transplant, or disease process with increased risk of causing early graft failure as assessed by the transplant nephrologist and/or the investigator team
- HIV positive
- Hepatitis B surface antigen positive
- HCV RNA positive (can be isolated HCV antibody positive)
- Any other chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD) with abnormal liver enzymes)
- Persistently elevated liver transaminases (ALT > 5 x ULN)
- Blood group AB(due to short expected waiting time on the kidney transplant waiting list)
- Significant hepatic fibrosis on screening elastography (> F2 fibrosis – LSM > 9.5 kPa)
Pregnant or nursing (lactating) women
- Known allergy or intolerance to tacrolimus that would require post- transplant administration of cyclosporine, rather than tacrolimus given the drug-drug interaction between cyclosporine and glecaprevir plus pibrentasvir
- Waitlisted for a multi-organ transplant (e.g., pancreas-kidney, heart-kidney,etc.)
- Cardiomyopathy (e.g., left-ventricular heart failure, pulmonary hypertension) that would preclude liver transplantation
Exclusion criteria – donor organ:
- Diabetes mellitus I or II
- Anatomical issues in the kidney allograft that raise the risk of post-transplant complications (e.g. number or length of renal arteries or veins)
- Confirmed HIV positive by NAT testing
- Confirmed HBV positive (positive hepatitis B surface antigen and/or NAT testing)
- Known previously failed treatment for HCV using a regimen with a direct-acting antiviral (can have received interferon monotherapy and/or interferon + ribavirin combination therapy)

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
n/a
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
n/a
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Statistical analysis
This is a pilot study and descriptive analysis only will be performed.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 18811 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 18812 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment postcode(s) [1] 31844 0
3065 - Fitzroy
Recruitment postcode(s) [2] 33260 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 307153 0
Hospital
Name [1] 307153 0
Gastroenterology Department, St Vincent's Hospital (Melbourne)
Address [1] 307153 0
41 Victoria Parade
Fitzroy, 3065, Victoria
Country [1] 307153 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital (Melbourne)
Address
41 Victoria Parade
Fitzroy, 3065, Victoria
Country
Australia
Secondary sponsor category [1] 307741 0
None
Name [1] 307741 0
n/a
Address [1] 307741 0
n/a
Country [1] 307741 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307266 0
St Vincent's Hospital (Melbourne) Human Research Ethics Committee
Ethics committee address [1] 307266 0
41 Victoria Parade
Fitzroy, 3065, Vic
Ethics committee country [1] 307266 0
Australia
Date submitted for ethics approval [1] 307266 0
22/05/2018
Approval date [1] 307266 0
10/09/2018
Ethics approval number [1] 307266 0
HREC/18/SVHM/180

Summary
Brief summary
This is a prospective, cohort study aiming to determine the feasibility of transplanting HCV positive kidneys into HCV negative recipients. The study team will identify potentially eligible subjects from the renal transplant waiting list. The study will be explained to them by both renal and gastroenterology study team members. Adequate time will be given for all questions to be answered to the participants complete satisfaction. Once the informed consent form has been signed, the subjects eligibility will be confirmed. When a HCV positive kidney becomes
available, the transplant will occur as per normal practice. As deemed clinically appropriate, as soon as possible after transplant the study subject will be commenced on a direct acting antiviral (DAA) treatment regimen of glecaprevir and pibrentasvir (g/p) for 12 weeks. The subjects normal, renal post-transplant inpatient and outpatient protocols will be followed. In addition, the subject will have follow-up with the Gastroenterology study team and additional blood samples will be taken to monitor HCV status and liver function. In particular, HCVRNA
will be monitored until expected HCVRNA clearance at week 12.
Trial website
n/a
Trial related presentations / publications
n/a
Public notes
n/a

Contacts
Principal investigator
Name 106626 0
A/Prof David Goodman
Address 106626 0
Department of Nephrology
St Vincent's Hospital (Melbourne)
41 Victoria Parade
Fitzroy, 3065, Vic
Country 106626 0
Australia
Phone 106626 0
+61 03 9231 3112
Fax 106626 0
+61 03 9231 3151
Email 106626 0
david.goodman@svha.org.au
Contact person for public queries
Name 106627 0
A/Prof David Goodman
Address 106627 0
Department of Nephrology
St Vincent's Hospital (Melbourne)
41 Victoria Parade
Fitzroy, 3065, Vic
Country 106627 0
Australia
Phone 106627 0
+61 03 9231 3112
Fax 106627 0
+61 03 9231 3151
Email 106627 0
david.goodman@svha.org.au
Contact person for scientific queries
Name 106628 0
A/Prof David Goodman
Address 106628 0
Department of Nephrology
St Vincent's Hospital (Melbourne)
41 Victoria Parade
Fitzroy, 3065, Vic
Country 106628 0
Australia
Phone 106628 0
+61 03 9231 3112
Fax 106628 0
+61 03 9231 3151
Email 106628 0
david.goodman@svha.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Principles of subject privacy prevent individual participant's data being made public.
What supporting documents are/will be available?
Informed consent form
How or where can supporting documents be obtained?
Type [1] 9655 0
Informed consent form
Citation [1] 9655 0
Link [1] 9655 0
Email [1] 9655 0
David.Goodman@svha.org.au
Other [1] 9655 0
Summary results
No Results