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

The study will consist of the following 4 treatment groups.:

1. Standard dose Advagraf with angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) antihypertensive therapy
2. Standard dose Advagraf without ACEi/ARB antihypertensive therapy
3. Low dose Advagraf with ACEi/ARB antihypertensive therapy
4. Low dose Advagraf without ACEi/ARB antihypertensive therapy

• tacrolimus (Drug), also known as Advagraf, FK506XL, Prolonged Release Tacrolimus, Tacrolimus XL, Extended Release Tacrolimus, FK506E, MR4: Standard dose, Oral
• tacrolimus (Drug), also known as Prolonged Release Tacrolimus, FK506XL, Extended Release Tacrolimus, Tacrolimus XL, FK506E, MR4, Advagraf: Low dose, Oral
• Simulect (Biological), also known as Basiliximab: IV
• Cellcept (Drug), also known as MMF: Oral
• Corticosteroids (Drug), also known as Methylprednisolone, prednisone: IV and Oral
• Ramipril (Drug), also known as Altace, ACEi: Oral
• Irbesartan (Drug), also known as Avapro, ARB: Oral

Primary outcomes

• 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 outcomes

• 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 [up to 24 months]: 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.
• 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) [up to 24 months]: 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.
• Kidney Transplant Recipient Opinions of Immunosuppressive Medications Questionnaire [up to 24 months]: 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.
• Percentage of Participants with Polyomavirus Infection [up to 12 months]

Sex: All, ages: 18 Years to any

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

• Results publication: Campbell PM, Cantarovich M, Gangji A, Houde I, Jevnikar AM, Monroy-Cuadros FM, Nickerson PW, Paquet MR, Prasad GVR, Senecal L, Wolff JL, Schwartz JJ, Rush DN. A Five-Year Prospective, Randomized, Open-Label Study of Standard-Dose Versus Low-Dose Prolonged-Release Tacrolimus With or Without Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker Post Kidney Transplantation. Clin Transplant. 2025 Jan;39(1):e70067. doi: 10.1111/ctr.70067. PMID 39739990
• Results publication: Natale P, Mooi PK, Palmer SC, Cross NB, Cooper TE, Webster AC, Masson P, Craig JC, Strippoli GF. Antihypertensive treatment for kidney transplant recipients. Cochrane Database Syst Rev. 2024 Jul 31;7(7):CD003598. doi: 10.1002/14651858.CD003598.pub3. PMID 39082471
• Results publication: Cockfield SM, Wilson S, Campbell PM, Cantarovich M, Gangji A, Houde I, Jevnikar AM, Keough-Ryan TM, Monroy-Cuadros FM, Nickerson PW, Paquet MR, Ramesh Prasad GV, Senecal L, Shoker A, Wolff JL, Howell J, Schwartz JJ, Rush DN. Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts. Am J Transplant. 2019 Jun;19(6):1730-1744. doi: 10.1111/ajt.15225. Epub 2019 Feb 1. PMID 30582281

• Principal Investigator, Principal investigator, University of Alberta
• Use Central Contact, Study director, Astellas Pharma Canada, Inc.