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Trial registered on ANZCTR


Registration number
ACTRN12611001224910
Ethics application status
Approved
Date submitted
25/11/2011
Date registered
29/11/2011
Date last updated
29/11/2011
Type of registration
Prospectively registered

Titles & IDs
Public title
REmoval Of Tacrolimus For Sirolimus Following Thymoglobulin Induction On The Development of REgulatory T Cells in Kidney Transplant Patients
Scientific title
A prospective, open label, controlled, multicentre trial to assess the effect of an induction regimen of Thymoglobulin (Registered Trademark) compared with Simulect (Registered Trademark) with Tacrolimus, Mycophenolic acid and corticosteroids, followed by withdrawal of Tacrolimus for Sirolimus on the development of regulatory T cells in kidney transplant recipients of donation after cardiac death donor kidneys
Secondary ID [1] 273467 0
Nil
Universal Trial Number (UTN)
Trial acronym
RESTORE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Development of circulating regulatory T cells 279254 0
Kidney transplant function, complications and biopsy 279255 0
Cardiovascular health 279256 0
Metabolic outcomes (glucose abnormality) 279257 0
Clinical significant infections and cancers 279258 0
Condition category
Condition code
Blood 279455 279455 0 0
Other blood disorders
Renal and Urogenital 279456 279456 0 0
Kidney disease
Cardiovascular 279457 279457 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Induction therapy with thymoglobulin with tacrolimus (0.15-0.20mg/kg/day in divided doses orally), mycophenolic acid (mycophenolate mofetil 1g twice daily or myfortic 720mg twice daily orally) and prednisolone (30mg daily orally), followed by changing from tacrolimus to sirolimus (2-5mg daily orally) in eligible patients (i.e. tacrolimus ceased and sirolimus commenced). Thymoglobulin given as 6mg/kg over 4 days as a 4-6 hour intravenous infusion, starting at time of transplant. Mycophenolic acid will be given pre-transplant and tacrolimus and prednisolone given within 12 hours post-transplant. The combination of tacrolimus (or sirolimus), mycophenolic acid and prednisolone will be given for at least 12 months following transplantation.

In more details:

Induction:
Thymoglobulin 6mg/kg in 4 divided doses.
Dose 1 – 1.5mg/kg given within 6 hours pre-transplant or at or around time of transplant as at least a 6 hour infusion (see appendix 2).
Dose 2 – 1.5mg/kg day +1 post-transplant as a 4-6 hours infusion.
Dose 3 – 1.5mg/kg day +2 post-transplant as a 4-6 hours infusion.
Dose 4 – 1.5mg/kg day +3 post-transplant as a 4-6 hours infusion.
Standard pre-transplant methylprednisolone (500-1000mg), day +1 methylprednisolone (500-1000mg) and day +2 oral prednisolone (30mg daily) to be given at least 30 minutes prior to thymoglobulin infusion with 1g paracetamol and 25mg oral/IM phernergan.
If the WCC is between 2-3x109/L and/or platelet count between 50-70x109/L, it is recommended that the dose of thymoglobulin is reduced by one-half. If the WCC is less than 2x109/L and/or platelet count is less than 50x109/L, it is recommended that thymoglobulin is stopped until the WCC and/or platelet counts recover.


Day 1 – Day 90-135:
Tacrolimus with dose adjusted to levels as per local institution protocol (recommended trough level 5-10ug/L).
Cellcept or myfortic - recommended dosing at least 1g bd or 720mg bd respectively for the first 2 weeks, then dosing according to local institutional protocol .
Prednisolone 30mg daily and dose reduce according to local institutional protocol to not less than 10mg daily.

Day 90 – Day 135 (conversion period):
Sirolimus: Recommendation is to stop tacrolimus on day before introducing sirolimus at 2-5mg daily. Target sirolimus trough level as per local protocol (recommendation: 8-12ug/L up to day 180). An overlap between tacrolimus and sirolimus is allowed and recommended regimen is to reduce tacrolimus by 50% and initiating sirolimus at 2mg daily. Tacrolimus must be ceased when sirolimus level reaches target level.
Cellcept or myfortic according to local institutional protocol.
Prednisolone as per local institution protocol.

Day 135 – month 12:
Sirolimus dose adjustment to achieve trough level as per local protocol (recommendation: target 8-12ug/L to day 180, then 5-10ug/L till month 12).
Cellcept or myfortic according to local institutional protocol.
Prednisolone as per local institution protocol.
Intervention code [1] 283785 0
Treatment: Drugs
Comparator / control treatment
Induction therapy with basiliximab with tacrolimus (0.15-0.20mg/kg/day in divided doses orally), mycophenolic acid (mycophenolate mofetil 1g twice daily or myfortic 720mg twice daily orally) and prednisolone (30mg daily orally), followed by changing from tacrolimus to sirolimus (2-5mg daily orally) in eligible patients (i.e. tacrolimus ceased and sirolimus commenced). Basiliximab given as two intravenous injection (20mg per dose) pre-transplant and day +4 post-transplant. Mycophenolic acid will be given pre-transplant and tacrolimus and prednisolone given within 12 hours post-transplant. The combination of tacrolimus (or sirolimus), mycophenolic acid and prednisolone will be given for at least 12 months following transplantation.

In more details:

Induction:

Basiliximab 20mg at day 0 (pre-transplant) and at day +4. Standard pre-transplant methylprednisolone (500-1000mg), day +1 methylprednisolone (500-1000mg) to be given followed by oral prednisolone (30mg daily) from day +2 post-transplant.

Day 1 – Day 90-135:
Tacrolimus with dose adjusted to levels as per local institution protocol (recommended trough level 5-10ug/L).
Cellcept or myfortic - recommended dosing at least 1g bd or 720mg bd for the first 2 weeks, then dosing according to local institutional protocol .
Prednisolone 30mg daily and dose reduce according to local institutional protocol to not less than 10mg daily.

Day 90 – Day 135 (conversion period):

Sirolimus: Recommendation is to stop tacrolimus on day before introducing sirolimus at 2-5mg daily. Target sirolimus trough level as per local protocol (recommendation: 8-12ug/L up to day 180). An overlap between tacrolimus and sirolimus is allowed and recommended regimen is to reduce tacrolimus by 50% and initiating sirolimus at 2mg daily. Tacrolimus must be ceased when sirolimus level reaches target level.
Cellcept or myfortic according to local institutional protocol.
Prednisolone as per local institution protocol.

Day 135 – month 12:
Sirolimus dose adjustment to achieve trough level as per local protocol (recommendation: target 8-12ug/L to day 180, then 5-10ug/L till month 12).
Cellcept or myfortic according to local institutional protocol.
Prednisolone as per local institution protocol.
Control group
Active

Outcomes
Primary outcome [1] 286016 0
Proportion of circulating regulatory T cells (CD4+CD25+FoxP3+) of peripheral blood mononuclear cells determined by flow cytometric analysis
Timepoint [1] 286016 0
Pre-transplant, 3 and 12 months post-transplant
Secondary outcome [1] 294984 0
Histology for chronic activity disease index (CADI) scoring and presence of chronic allograft nephropathy on transplant kidney biopsy
Timepoint [1] 294984 0
Implantation, 3 and 12 months post-transplant
Secondary outcome [2] 294985 0
Glucose regulation in non-diabetics assessed by an oral glucose tolerance test (blood glucose taken at time 0, 1 and 2 hours following a 75g oral glucose load)
Timepoint [2] 294985 0
3 and 12 months post-transplant
Secondary outcome [3] 294986 0
Effect of treatment on cardiovascular health including fasting serum lipids (LDL, HDL, triglycerides, total cholesterol), waist circumference (clinical measurement), blood pressure (average of 3 blood pressure readings 5 minutes apart with patient in sitting position) and cardiovascular events (clinical history)
Timepoint [3] 294986 0
3 and 12 months post-transplant
Secondary outcome [4] 294987 0
Inflammatory markers including serum C-reactive protein (blood test)
Timepoint [4] 294987 0
3 and 12 months post-transplant
Secondary outcome [5] 294988 0
Development of de novo anti-HLA donor-specific antibodies (blood test)
Timepoint [5] 294988 0
3 and 12 months post-transplant
Secondary outcome [6] 294989 0
Transplant kidney function determined by radionuclide scan and proteinuria determined by spot urine protein/creatinine ratio
Timepoint [6] 294989 0
3 and 12 months post-transplant
Secondary outcome [7] 294990 0
Transplant kidney complications including rejection, wound problems, haematological abnormalities, graft survival, infections and malignancies (clinical assessments)
Timepoint [7] 294990 0
3 and 12 months post-transplant
Secondary outcome [8] 294991 0
Death (clinical assessments)
Timepoint [8] 294991 0
3 and 12 months post-transplant

Eligibility
Key inclusion criteria
Inclusion criteria at randomisation:
1. Males and females aged >18 years inclusive.
2. Primary and subsequent DCD renal transplant recipients.
3. Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at screening, and are required to practice a medically accepted effective method of birth control for the duration of the study and for a period of 6 weeks following discontinuation of study medication, even where there has been a history of infertility.
4. Patients who are willing and able to participate in the study and from whom written informed consent has been obtained.

Inclusion criteria for conversion:

1. Day 90-135 post-kidney transplantation.
2. Continuously maintained on Tacrolimus and Mycophenolic acid during the last 30 days.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria at randomisation:
1. Patients who are recipients of multiple organ transplants, kidney and pancreas, or previous transplant with any organ other than kidney but recipients receiving two kidneys from DCD donor can be included in study.
2. Patients at high immunological risk of graft loss, indicated by the presence of donor-specific antibody or loss of a previous renal allograft within the first 6 months of transplantation due to acute rejection.
3. Presence of any severe allergy or hypersensitivity to drugs similar to sirolimus (e.g. macrolides), tacrolimus, thymoglobulin, basiliximab or mycophenolic acid.
4. Patients who are recipients of A-B-O incompatible transplants or T or B cell allogeneic cross-match positive transplants.
5. Patients who are known to have chronic active Hepatitis C, or who are HIV or Hepatitis B surface antigen positive. Laboratory results obtained within 6 months prior to randomization are acceptable. Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C are excluded.
6. Patients with symptoms of significant somatic or mental illness, or inability to co-operate or communicate with the investigator.
7. Unresolved history of drug or alcohol abuse.
8. Patients with clinically significant infections requiring continued therapy, severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus that in the opinion of the investigator would interfere with the appropriate conduct of the study.
9. Patients with a history of malignancy within 3 years of transplant (other than excised basal cell carcinoma of the skin).
10. Breastfeeding women.
11. Abnormal physical or laboratory findings of clinical significance, which at investigator discretion would interfere with the objectives of the study.
12. Patients receiving drugs known to interact with tacrolimus and/or sirolimus, where exposure to the interacting drug is unstable/variable or may lead to difficulties attaining stable target levels of tacrolimus or sirolimus.


Exclusion Criteria at conversion:

1. 3-month biopsy demonstrating subclinical/grade I rejection, recurrent glomerular disease and/or transplant glomerulopathy (patients with subclinical rejection or with grade I rejection may still be included provided they have a normal repeat biopsy within the conversion period. The repeat biopsy should occur at least 14 days after the last dose of methylprednisolone and at least 7 days prior to the conversion to sirolimus).

2. Any vascular or antibody-mediated or = grade 2 rejection according to Banff criteria at any time prior to conversion.

3. Patients treated with other immunosuppressive agents not described in this protocol (e.g. cyclosporine, everolimus).
4. Significant proteinuria (defined as equivalent to protein/creatinine ratio >80mg/mmol) within 1 week prior to randomization.
5. eGFR (4-point MDRD) of <35ml/min.
6. Patients with thrombocytopenia (platelets <75,000/mm3), with an absolute neutrophil count of <1,500/mm3 or leucopenia (leucocytes <2,500/mm3), or hemoglobin <8g/dL.
7. Evidence of severe liver disease (including abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin >3 times ULN).
8. Patients with fasting total cholesterol >8mmol/L and/or triglyceride >4.5mmol/L despite lipid-lowering agents.
9. Recent major surgery within 2 weeks prior to conversion to sirolimus.

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)
Randomization pre-transplant (study 1) will be performed by an authorized co-investigator and/or research staff not directly involved in the care of the patients pre- and post-kidney transplantation. The investigator will receive a set of treatment allocation cards with sequential randomization numbers on which a label covers the treatment group information or cards are contained within an envelope. The treatment allocation cards are used to avoid bias in the assignment of the patients to Group 1 and Group 2 in the specified 1:1 ratio.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequential randomization numbers
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2012
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 284261 0
Commercial sector/Industry
Name [1] 284261 0
Genzyme Australia
Country [1] 284261 0
Australia
Funding source category [2] 284262 0
Commercial sector/Industry
Name [2] 284262 0
Pfizer Australia
Country [2] 284262 0
Australia
Primary sponsor type
Government body
Name
Department of Health
Address
189 Royal Street, East Perth WA 6004
Country
Australia
Secondary sponsor category [1] 269214 0
None
Name [1] 269214 0
Address [1] 269214 0
Country [1] 269214 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286222 0
Sir Charles Gairdner Hospital Group
Ethics committee address [1] 286222 0
Ethics committee country [1] 286222 0
Australia
Date submitted for ethics approval [1] 286222 0
Approval date [1] 286222 0
23/11/2011
Ethics approval number [1] 286222 0
2010-019

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

Contacts
Principal investigator
Name 33438 0
Address 33438 0
Country 33438 0
Phone 33438 0
Fax 33438 0
Email 33438 0
Contact person for public queries
Name 16685 0
Dr Wai Lim
Address 16685 0
Department of Renal Medicine
Sir Charles Gairdner Hospital
Hospital Avenue,
NEDLANDS WA 6009
Country 16685 0
Australia
Phone 16685 0
+61 8 93462799
Fax 16685 0
+61 8 93463942
Email 16685 0
[email protected]
Contact person for scientific queries
Name 7613 0
Dr Wai Lim
Address 7613 0
Department of Renal Medicine
Sir Charles Gairdner Hospital
Hospital Avenue,
NEDLANDS WA 6009
Country 7613 0
Australia
Phone 7613 0
+61 8 93462799
Fax 7613 0
+61 8 93463942
Email 7613 0
[email protected]

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