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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Factorial Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: May 11, 2015

Detailed Description

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

Interventions

  • Drug: tacrolimus
    • Standard dose, Oral
  • Drug: tacrolimus
    • Low dose, Oral
  • Biological: Simulect
    • IV
  • Drug: Cellcept
    • Oral
  • Drug: Corticosteroids
    • IV and Oral
  • Drug: Ramipril
    • Oral
  • Drug: Irbesartan
    • Oral

Arms, Groups and Cohorts

  • Active Comparator: Tacrolimus Standard Dose with ACEi/ARB
    • Participants receive a standard dose of tacrolimus with ACEi/ARB.
  • Active Comparator: Tacrolimus Standard Dose without ACEi/ARB
    • Participants receive a standard dose of tacrolimus without ACEi/ARB.
  • Experimental: Tacrolimus Low Dose with ACEi/ARB
    • Participants receive a low dose of tacrolimus with ACEi/ARB.
  • Experimental: Tacrolimus Low Dose without ACEi/ARB
    • Participants receive a low dose of tacrolimus without ACEi/ARB.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • Time to T-cell Banff Mediated Rejection as Assessed at a Central Pathology Lab
    • Time Frame: up to 24 months
  • Percentage of Participants in Each Category of Banff 2007 Diagnostic Classification of Renal Allograft Pathology
    • Time Frame: up to 24 months
  • Percentage of Participants with Humoral Rejections
    • Time Frame: up to 24 months
  • Percentage of Participants with Acute Rejections
    • Time Frame: up to 24 months
  • Time to First Any Acute Rejection
    • Time Frame: up to 24 months
  • Banff 2007 Individual Sub-scores
    • Time Frame: 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
    • Time Frame: Baseline and 6, 24 months
  • Percentage of Participants with Circulating Anti-Donor Antibody
    • Time Frame: up to 5 years
  • Number of Participants with Cellular Immune Response (ELISPOT)
    • Time Frame: up to 6 months
  • Urine Renal Biomarkers
    • Time Frame: up to 24 months
  • Graft Survival
    • Time Frame: up to 5 years
  • Patient Survival
    • Time Frame: up to 5 years
  • Renal Function as Measured by Glomerular Filtration Rate (GFR)
    • Time Frame: up to 5 years
  • Renal Function as Measured by Serum Creatinine
    • Time Frame: up to 5 years
  • Renal Function as Measured by Ratio of Urine Protein and Creatinine Concentrations
    • Time Frame: up to 5 years
  • 12-Item Short Form (SF-12) Health Survey: Physical Composite Score (PCS) and Mental Health Composite Score (MCS)
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: up to 12 months

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Astellas Pharma Inc
  • Collaborator
    • Astellas Pharma Canada, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Principal Investigator, Principal Investigator, University of Alberta
    • Use Central Contact, Study Director, Astellas Pharma Canada, Inc.

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