Comparison of Standard Versus Low Dose Advagraf® With or Without Angiotensin-converting Enzyme Inhibitor (ACEi)/Angiotensin Receptor Blocker (ARB) on Histology and Function of Renal Allografts

Study Overview
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Brief Summary
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This is a multicentre study examining the use of Advagraf-minimization strategy and/or the use of an inhibitor of the renin-angiotensin system in reducing chronic rejection in renal allografts.

Detailed Description
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The study will consist of the following 4 treatment groups.: Standard dose Advagraf with angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) antihypertensive therapy Standard dose Advagraf without ACEi/ARB antihypertensive therapy Low dose Advagraf with ACEi/ARB antihypertensive therapy Low dose Advagraf without ACEi/ARB antihypertensive therapy

Official Title
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A Comparison of Effects of Standard Dose vs. Low Dose Advagraf® With IL-2 Receptor Antibody Induction, MMF and Steroids, With or Without ACEi/ARB - Based Antihypertensive Therapy on Renal Allograft Histology, Function, and Immune Response

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: tacrolimus
* Drug: tacrolimus
* Biological: Simulect
* Drug: Cellcept
* Drug: Corticosteroids
* Drug: Ramipril
* Drug: Irbesartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is the recipient of a first or second deceased or living donor renal transplant (one kidney only) Subject must have at least one HLA-mismatch with the donor. HLA identical donor-recipient pairs are not eligible Subject understands either English or French If female and of child-bearing potential, subject has a negative pregnancy test and utilizes adequate contraceptive methods Exclusion Criteria: Presence of donor specific antibody Subject who is currently participating in a study with investigational drug, or who has received investigational drug within three months prior to randomization. Observational studies are acceptable Subject who has lost a previous graft for immunological reasons less than one year from transplant Subject is pregnant or breastfeeding Subject receives a kidney lacking pre-implantation biopsy Subject has significant disease (e.g. malignancy or uncontrolled infection) or disability (e.g. cognitive defect) which prevents understanding of, or adherence to the protocol Subject who in the opinion of the Investigator, require ACEi/ARB therapy post-transplant for any indication Subject who requires induction with Thymoglobulin, Campath, antithymocyte globulin (ATG), antilymphocyte globulin (ALG) or any biological induction agent other than basiliximab. Unplanned post-transplant use of these prohibited drugs for clinical indications post-transplant is allowed Subject has plans to become pregnant within 2 years post-transplant Subject who has a positive T-cell or B-cell crossmatch. Subjects with a weakly positive B-cell cross-match that tests negative following DTT reduction are acceptable Subject who has a requirement for maintenance immunosuppressant therapy with the exception of low dose steroid or mycophenolate mofetil (MMF). A subject who is on low dose tacrolimus maintenance therapy will be eligible provided the tacrolimus is withheld at least 1 week prior to transplant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tacrolimus Standard Dose with ACEi/ARB<br>Participants receive a standard dose of tacrolimus with ACEi/ARB. | Drug: tacrolimus<br>* Standard dose, Oral<br>* Other names: MR4;Biological: Simulect<br>* IV<br>* Other names: Basiliximab;Drug: Cellcept<br>* Oral<br>* Other names: MMF;Drug: Corticosteroids<br>* IV and Oral<br>* Other names: prednisone;Drug: Ramipril<br>* Oral<br>* Other names: ACEi;Drug: Irbesartan<br>* Oral<br>* Other names: ARB;|
| Active Comparator: Tacrolimus Standard Dose without ACEi/ARB<br>Participants receive a standard dose of tacrolimus without ACEi/ARB. | Drug: tacrolimus<br>* Standard dose, Oral<br>* Other names: MR4;Biological: Simulect<br>* IV<br>* Other names: Basiliximab;Drug: Cellcept<br>* Oral<br>* Other names: MMF;Drug: Corticosteroids<br>* IV and Oral<br>* Other names: prednisone;|
| Experimental: Tacrolimus Low Dose with ACEi/ARB<br>Participants receive a low dose of tacrolimus with ACEi/ARB. | Drug: tacrolimus<br>* Low dose, Oral<br>* Other names: Advagraf;Biological: Simulect<br>* IV<br>* Other names: Basiliximab;Drug: Cellcept<br>* Oral<br>* Other names: MMF;Drug: Corticosteroids<br>* IV and Oral<br>* Other names: prednisone;Drug: Ramipril<br>* Oral<br>* Other names: ACEi;Drug: Irbesartan<br>* Oral<br>* Other names: ARB;|
| Experimental: Tacrolimus Low Dose without ACEi/ARB<br>Participants receive a low dose of tacrolimus without ACEi/ARB. | Drug: tacrolimus<br>* Low dose, Oral<br>* Other names: Advagraf;Biological: Simulect<br>* IV<br>* Other names: Basiliximab;Drug: Cellcept<br>* Oral<br>* Other names: MMF;Drug: Corticosteroids<br>* IV and Oral<br>* Other names: prednisone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with the Presence of Allograft Interstitial Fibrosis and Tubular Atrophy (IF/TA) as Assessed at a Central Pathology Lab |  | up to 24 months | 
| Progression of IF/TA from Month 6 to Month 24 |  | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to T-cell Banff Mediated Rejection as Assessed at a Central Pathology Lab |  | up to 24 months | 
| Percentage of Participants in Each Category of Banff 2007 Diagnostic Classification of Renal Allograft Pathology |  | up to 24 months | 
| Percentage of Participants with Humoral Rejections |  | up to 24 months | 
| Percentage of Participants with Acute Rejections |  | up to 24 months | 
| Time to First Any Acute Rejection |  | up to 24 months | 
| Banff 2007 Individual Sub-scores | Banff 2007 sub-scores (AH = Arteriolar hyalinethickening score; AT = Tubulitis score; AV = Intimal arteritis score; AI = Interstitial inflammation score; AG = Glomerulitis score; CG = Glomerulopathy score; CI = Interstitial fibrosis score; CT = Tubularatrophy score; CV = Vascular fibrous intimal thickening score; MM = Mesangial matrix increase score; TI = Total interstitial inflammation score; PTC = Peritubulary capillaritis score) is measured on an ordinal scale of 0 - 3. | up to 24 months | 
| Change from Baseline in Chronic Allograft Damage Index |  | Baseline and 6, 24 months | 
| Percentage of Participants with Circulating Anti-Donor Antibody |  | up to 5 years | 
| Number of Participants with Cellular Immune Response (ELISPOT) |  | up to 6 months | 
| Urine Renal Biomarkers |  | up to 24 months | 
| Graft Survival |  | up to 5 years | 
| Patient Survival |  | up to 5 years | 
| Renal Function as Measured by Glomerular Filtration Rate (GFR) |  | up to 5 years | 
| Renal Function as Measured by Serum Creatinine |  | up to 5 years | 
| Renal Function as Measured by Ratio of Urine Protein and Creatinine Concentrations |  | up to 5 years | 
| 12-Item Short Form (SF-12) Health Survey: Physical Composite Score (PCS) and Mental Health Composite Score (MCS) | The PCS and MCS are measured on a normalized 0-100 scale and computed using the corresponding subdomains from the SF-12 with 0 being the lowest level of health and 100 the highest. | up to 24 months | 
| Kidney Transplant Recipient Opinions of Immunosuppressive Medications Questionnaire | This questionnaire consists of 11 questions regarding immunosuppressive medications, where questions 1-3 ask about your experiences and opinions of transplant anti-rejection medications, questions 4 and 11 ask to rate each medication on the scale of 1-10, with 1 meaning disagree completely and 10 meaning agree completely, and questions 5-10 ask which medication satisfies the question. | up to 24 months | 
| Percentage of Participants with Polyomavirus Infection |  | up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tacrolimus, Kidney Transplantation, Advagraf, Immunosuppression, Angiotensin-Converting Enzyme Inhibitors