Clinical trial NCT00933231: 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
Official title: 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: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Kidney Transplantation
Keywords: Tacrolimus
Kidney Transplantation
Advagraf
Immunosuppression
Angiotensin-Converting Enzyme Inhibitors
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Astellas Pharma Canada, Inc.
First posted: 2009-07-07
Enrollment: 281
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants with the Presence of Allograft Interstitial Fibrosis and Tubular Atrophy (IF/TA) as Assessed at a Central Pathology Lab
timeFrame: up to 24 months
measure: Progression of IF/TA from Month 6 to Month 24
timeFrame: up to 24 months
Secondary outcomes:
measure: Time to T-cell Banff Mediated Rejection as Assessed at a Central Pathology Lab
timeFrame: up to 24 months
measure: Percentage of Participants in Each Category of Banff 2007 Diagnostic Classification of Renal Allograft Pathology
timeFrame: up to 24 months
measure: Percentage of Participants with Humoral Rejections
timeFrame: up to 24 months
measure: Percentage of Participants with Acute Rejections
timeFrame: up to 24 months
measure: Time to First Any Acute Rejection
timeFrame: up to 24 months
measure: Banff 2007 Individual Sub-scores
timeFrame: up to 24 months
measure: Change from Baseline in Chronic Allograft Damage Index
timeFrame: Baseline and 6, 24 months
measure: Percentage of Participants with Circulating Anti-Donor Antibody
timeFrame: up to 5 years
measure: Number of Participants with Cellular Immune Response (ELISPOT)
timeFrame: up to 6 months
measure: Urine Renal Biomarkers
timeFrame: up to 24 months
measure: Graft Survival
timeFrame: up to 5 years
measure: Patient Survival
timeFrame: up to 5 years
measure: Renal Function as Measured by Glomerular Filtration Rate (GFR)
timeFrame: up to 5 years
measure: Renal Function as Measured by Serum Creatinine
timeFrame: up to 5 years
measure: Renal Function as Measured by Ratio of Urine Protein and Creatinine Concentrations
timeFrame: up to 5 years
measure: 12-Item Short Form (SF-12) Health Survey: Physical Composite Score (PCS) and Mental Health Composite Score (MCS)
timeFrame: up to 24 months
measure: Kidney Transplant Recipient Opinions of Immunosuppressive Medications Questionnaire
timeFrame: up to 24 months
measure: Percentage of Participants with Polyomavirus Infection
timeFrame: up to 12 months
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Site CA133 Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: Site CA54 University of Alberta Hospital
state: Alberta
city: Winnipeg
country: Canada
facility: Site CA141 Health Sciences Centre
state: Manitoba
city: Halifax
country: Canada
facility: Site CA114 Capital District Health Authority- QEII Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Site CA150 St. Joseph's Healthcare
state: Ontario
city: London
country: Canada
facility: Site CA27 London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Site CA165 St. Michael's Hospital
state: Ontario
city: Montreal
country: Canada
facility: Site CA238 Hôpital Maisonneuve-Rosemont
state: Quebec
city: Montreal
country: Canada
facility: Site CA172 Hôpital Notre-Dame du CHUM
state: Quebec
city: Montreal
country: Canada
facility: Site CA144 McGill University Health Centre
state: Quebec
city: Sherbrooke
country: Canada
facility: Site CA116 Centre Hospitalier Universitaire de Sherbrooke- Hôpital Fleuirmont
state: Quebec
city: Saskatoon
country: Canada
facility: Site CA142 St. Paul's Hospital
state: Saskatchewan
city: Quebec
country: Canada
facility: Site CA64 Centre Hospitalier Universitaire de Québec- L'Hôtel-dieu de Québec
Study officials:
affiliation: University of Alberta
name: Principal Investigator
role: PRINCIPAL_INVESTIGATOR
affiliation: Astellas Pharma Canada, Inc.
name: Use Central Contact
role: STUDY_DIRECTOR
References:
citation: 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.