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

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

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.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: tacrolimus; Drug: tacrolimus; Biological: Simulect; Drug: Cellcept; Drug: Corticosteroids; Drug: Ramipril; Drug: Irbesartan

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

• Study Type: Interventional
• Enrollment (Actual): 281
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1R 2J6
    • Site CA64 Centre Hospitalier Universitaire de Québec- L'Hôtel-dieu de Québec
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Site CA133 Foothills Medical Centre
    • Edmonton, Alberta, Canada, T6G 2B7
      • Site CA54 University of Alberta Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Site CA141 Health Sciences Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Site CA114 Capital District Health Authority- QEII Health Sciences Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Site CA150 St. Joseph's Healthcare
    • London, Ontario, Canada, N6A 5A5
      • Site CA27 London Health Sciences Centre
    • Toronto, Ontario, Canada, M5C 2T2
      • Site CA165 St. Michael's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Site CA238 Hôpital Maisonneuve-Rosemont
    • Montreal, Quebec, Canada, H2L 4M1
      • Site CA172 Hôpital Notre-Dame du CHUM
    • Montreal, Quebec, Canada, H4A 3J1
      • Site CA144 McGill University Health Centre
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Site CA116 Centre Hospitalier Universitaire de Sherbrooke- Hôpital Fleuirmont
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7V 0Z9
      • Site CA142 St. Paul's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tacrolimus Standard Dose with ACEi/ARB; Participants receive a standard dose of tacrolimus with ACEi/ARB.	Drug: tacrolimus; Standard dose, Oral; Other Names: Advagraf; FK506E; MR4; Extended Release Tacrolimus; FK506XL; Prolonged Release Tacrolimus; Tacrolimus XL; Drug: tacrolimus; Low dose, Oral; Other Names: Advagraf; FK506E; MR4; Extended Release Tacrolimus; FK506XL; Prolonged Release Tacrolimus; Tacrolimus XL; Biological: Simulect; IV; Other Names: Basiliximab; Drug: Cellcept; Oral; Other Names: MMF; Drug: Corticosteroids; IV and Oral; Other Names: Methylprednisolone; prednisone; Drug: Ramipril; Oral; Other Names: Altace; ACEi; Drug: Irbesartan; Oral; Other Names: Avapro; ARB
Active Comparator: Tacrolimus Standard Dose without ACEi/ARB; Participants receive a standard dose of tacrolimus without ACEi/ARB.	Drug: tacrolimus; Standard dose, Oral; Other Names: Advagraf; FK506E; MR4; Extended Release Tacrolimus; FK506XL; Prolonged Release Tacrolimus; Tacrolimus XL; Drug: tacrolimus; Low dose, Oral; Other Names: Advagraf; FK506E; MR4; Extended Release Tacrolimus; FK506XL; Prolonged Release Tacrolimus; Tacrolimus XL; Biological: Simulect; IV; Other Names: Basiliximab; Drug: Cellcept; Oral; Other Names: MMF; Drug: Corticosteroids; IV and Oral; Other Names: Methylprednisolone; prednisone
Experimental: Tacrolimus Low Dose with ACEi/ARB; Participants receive a low dose of tacrolimus with ACEi/ARB.	Drug: tacrolimus; Standard dose, Oral; Other Names: Advagraf; FK506E; MR4; Extended Release Tacrolimus; FK506XL; Prolonged Release Tacrolimus; Tacrolimus XL; Drug: tacrolimus; Low dose, Oral; Other Names: Advagraf; FK506E; MR4; Extended Release Tacrolimus; FK506XL; Prolonged Release Tacrolimus; Tacrolimus XL; Biological: Simulect; IV; Other Names: Basiliximab; Drug: Cellcept; Oral; Other Names: MMF; Drug: Corticosteroids; IV and Oral; Other Names: Methylprednisolone; prednisone; Drug: Ramipril; Oral; Other Names: Altace; ACEi; Drug: Irbesartan; Oral; Other Names: Avapro; ARB
Experimental: Tacrolimus Low Dose without ACEi/ARB; Participants receive a low dose of tacrolimus without ACEi/ARB.	Drug: tacrolimus; Standard dose, Oral; Other Names: Advagraf; FK506E; MR4; Extended Release Tacrolimus; FK506XL; Prolonged Release Tacrolimus; Tacrolimus XL; Drug: tacrolimus; Low dose, Oral; Other Names: Advagraf; FK506E; MR4; Extended Release Tacrolimus; FK506XL; Prolonged Release Tacrolimus; Tacrolimus XL; Biological: Simulect; IV; Other Names: Basiliximab; Drug: Cellcept; Oral; Other Names: MMF; Drug: Corticosteroids; IV and Oral; Other Names: Methylprednisolone; prednisone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Collaborators: Astellas Pharma Canada, Inc.
• Investigators: Principal Investigator: Principal Investigator, University of Alberta

Publications and helpful links

General Publications

• 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.

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2009
• Primary Completion (Actual): May 11, 2015
• Study Completion (Actual): April 3, 2018

Study Registration Dates

• First Submitted: July 2, 2009
• First Submitted That Met QC Criteria: July 6, 2009
• First Posted (Estimate): July 7, 2009

Study Record Updates

• Last Update Posted (Actual): April 5, 2019
• Last Update Submitted That Met QC Criteria: April 3, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Immunosuppression; Tacrolimus; Kidney Transplantation; Advagraf; Angiotensin-Converting Enzyme Inhibitors
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Antitubercular Agents; Angiotensin-Converting Enzyme Inhibitors; Antibiotics, Antitubercular; Calcineurin Inhibitors; Methylprednisolone; Prednisone; Tacrolimus; Mycophenolic Acid; Basiliximab; Ramipril; Irbesartan
• Other Study ID Numbers: FKC-014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the trial, in addition to study-related supporting documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No