A Study Looking at Kidney Function in Kidney Transplant Recipients Who Are Taking Anti-rejection Medication Including Tacrolimus and With or Without Sirolimus. (ADHERE)

A Multicenter, Two Arm, Randomized, Open Label Clinical Study Investigating Renal Function in an Advagraf® Based Immunosuppressive Regimen With or Without Sirolimus in Kidney Transplant Patients

The purpose of this study is to compare the effect of two anti-rejection therapy regimens on kidney function in kidney transplant recipients.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Mycophenolate Mofetil; Drug: Advagraf; Drug: Corticosteroids; Drug: Sirolimus

Detailed Description

This study will evaluate the potential to reduce nephrotoxic calcineurin inhibitors (CNI) therapy by lowering tacrolimus exposure from Advagraf® in combination with the non-nephrotoxic immunosuppressant sirolimus to avoid the risk of acute graft rejection, compared with an Advagraf® and Mycophenolate Mofetil (MMF) immunosuppressive regimen.

• Study Type: Interventional
• Enrollment (Actual): 853
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New Lambton, Australia, NSW 2305
    • 5042
  • Perth, Australia, WA 6009
    • 5043
• Austria
  • Innsbruck, Austria, 6020
    • 1141
  • Linz, Austria, 4020
    • 1142
  • Vienna, Austria, 1090
    • 1140
• Belarus
  • Minsk, Belarus, 220116
    • 3240
• Belgium
  • Leuven, Belgium, 3000
    • 1241
  • Liege 1, Belgium, 4000
    • 1240
• Czechia
  • Brno, Czechia, 656 91
    • Site 1441
  • Ostrava - Poruba, Czechia, 78 52
    • 1440
• France
  • Amiens Cedex, France, 80054
    • 1752
  • Brest Cedex 2, France, 29609
    • 1740
  • Clermont-Ferrand Cedex 1, France, 63003
    • 1742
  • Creteil Cedex, France, 94010
    • 1746
  • Dijon, France, 21000
    • 1750
  • Le Kremilin Bicetre Cedex, France, 94275
    • 1741
  • Paris Cedex 15, France, 75743
    • 1749
  • Toulouse Cedex 9, France, 31059
    • 1751
  • Tours cedex 9, France, 37044
    • 1748
  • Vandoeuvre Les Nancy Cedex, France, 54511
    • 1745
• Germany
  • Bochum, Germany, 44892
    • 1541
  • Erlangen, Germany, 91054
    • 1542
  • Essen, Germany, 45147
    • 1543
  • Frankfurt, Germany, 60596
    • 1544
  • Hann.Munden, Germany, 34346
    • 1545
  • Hannover, Germany, 30625
    • 1540
  • Heidelberg, Germany, 69120
    • 1546
  • Kiel, Germany, 24105
    • 1547
  • Leipzig, Germany, 04103
    • 1548
  • Munchen, Germany, 81377
    • 1549
  • Munster, Germany, 48149
    • 1550
• Hong Kong
  • Hong Kong, Hong Kong
    • 5441
• Hungary
  • Budapest, Hungary, 1082
    • 1940
• Italy
  • Palermo, Italy, 90124
    • 2144
  • Roma, Italy, 00168
    • 2143
  • Siena, Italy, 53100
    • 2140
• Korea, Republic of
  • Busan, Korea, Republic of, 614-735
    • 5245
  • Daegu, Korea, Republic of, 700-721
    • 5243
  • Seoul, Korea, Republic of, 110-744
    • 5242
  • Seoul, Korea, Republic of, 120-752
    • 5241
  • Seoul, Korea, Republic of, 138-736
    • 5244
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • 2440
• Poland
  • Katowice, Poland, 40-027
    • 2643
  • Lodz, Poland, 91-153
    • 2640
  • Poznan, Poland, 60-479
    • 2641
• Russian Federation
  • Kemerovo, Russian Federation, 650066
    • 2841
  • Moscow, Russian Federation, 115446
    • 2843
  • Omsk, Russian Federation, 644112
    • 2842
  • Vol'ginskiy, Russian Federation, 404120
    • 2840
• Spain
  • Alicante, Spain, 03010
    • 1640
  • Barcelona, Spain, 08907
    • 1641
  • Santander, Spain, 39008
    • 1643
  • Vizcaya, Spain, 48903
    • 1642
• Taiwan
  • Tainan, Taiwan, 70403
    • 5343
  • Taoyuan, Taiwan, 33305
    • 5342
• Turkey
  • Istanbul, Turkey, 07058
    • 3042
  • Istanbul, Turkey, 34245
    • 3043
  • Istanbul, Turkey, 34732
    • 3044

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• End stage kidney disease and a suitable candidate for primary renal transplantation or re-transplantation (unless the graft was lost from rejection within 6 months)
• Receiving a kidney transplant from a deceased or living (non Human Leukocyte Antigen [HLA] identical) donor with compatible ABO blood type
• Female subject of childbearing potential has a negative serum or urine pregnancy test at enrollment
• Female and male subjects agree to maintain highly effective birth control during the study and for 90 days after discontinuation of dosing with study drugs. A highly effective method of birth control is defined as those which result in a low failure rate (CPMP/ ICH/ 286/ 95 modified) of less than 1% per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some Intrauterine Devises (IUDs), sexual abstinence or vasectomized partner

Exclusion Criteria:

• Receiving or having previously received an organ transplant other than a kidney
• Cold ischemia time of the donor kidney > 30 hours
• Panel Reactive Antibody (PRA) >20%
• Receiving a graft from a non-heart-beating donor other than of Maastricht category 3 (withdrawal of support awaiting cardiac arrest)
• Significant liver disease, defined as having continuously elevated SGPT/ ALT and/ or SGOT/ AST and/ or total bilirubin levels ≥ 2 times the upper value of the normal range of the investigational site or is receiving a graft from a hepatitis C or B positive donor
• Requiring initial sequential or parallel therapy with immunosuppressive antibody preparation(s)
• Requiring ongoing dosing with a systemic immunosuppressive drug prior to transplantation (other than minimal levels of immunosuppression following failure of previous transplantation without nephrectomy)
• Significant, uncontrolled concomitant infections and/ or severe diarrhea, vomiting, active upper gastro-intestinal tract malabsorption or active peptic ulcer
• Pregnant woman or breast-feeding mother
• Subject or donor known to be HIV positive
• Known allergy or intolerance to tacrolimus, macrolide antibiotics, corticosteroids, sirolimus, MMF or any of the product excipients or iodine
• Evidence of malignant disease within the last 5 years, not including non-malignant skin cancers
• Currently participating in another clinical trial, and/ or has taken an investigational drug within 28 days prior to enrollment
• Unlikely to comply with the visits scheduled in the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Advagraf + MMF + Steroids; Without sirolimus	Drug: Mycophenolate Mofetil; oral; Other Names: CellCept; Drug: Advagraf; oral; Other Names: FK506E; Prolonged release tacrolimus; Drug: Corticosteroids; i.v. and oral
Experimental: Advagraf + MMF + Steroids + Sirolimus; With sirolimus; MMF withdrawn on Day 28; Sirolimus introduced on Day 28	Drug: Mycophenolate Mofetil; oral; Other Names: CellCept; Drug: Advagraf; oral; Other Names: FK506E; Prolonged release tacrolimus; Drug: Corticosteroids; i.v. and oral; Drug: Sirolimus; oral; Other Names: Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Glomerular Filtration Rate (GFR) estimated by iohexol clearance at Week 52 post kidney transplantation	up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy failure	Composite endpoint defined as graft loss (re-transplantation, nephrectomy, death or dialysis ongoing at the study end) or subject withdrawal	up to 1 year
GFR at Week 52 post kidney transplantation by Modification Diet in Renal Disease (MDRD) formula		up to 1 year
GFR at Week 52 post kidney transplantation by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula		up to 1 year
Calculated creatinine clearance at Week 52 post kidney transplantation by Cockcroft and Gault formula		up to 1 year
Incidence of clinical acute rejection		up to 1 year
Time to clinical acute rejection		up to 1 year
Incidence of Biopsy Confirmed Acute Rejection		up to 1 year
Time to Biopsy Confirmed Acute Rejection		up to 1 year
Subject survival		up to 1 year
Graft survival		up to 1 year
New Onset Diabetes Mellitus (NODM) as per American Diabetic Association (ADA) criteria		up to 1 year

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Investigators: Study Director: Use Central Contact, Astellas Pharma Europe Ltd.

Publications and helpful links

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2011
• Primary Completion (Actual): September 18, 2013
• Study Completion (Actual): September 18, 2013

Study Registration Dates

• First Submitted: May 31, 2011
• First Submitted That Met QC Criteria: May 31, 2011
• First Posted (Estimated): June 2, 2011

Study Record Updates

• Last Update Posted (Actual): October 31, 2024
• Last Update Submitted That Met QC Criteria: October 29, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Immunosuppression; Tacrolimus; Transplant; Kidney; Kidney Failure, Acute; Astagraf XL; Advagraf
• Additional Relevant MeSH Terms: Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antibiotics, Antitubercular; Antitubercular Agents; Calcineurin Inhibitors; Sirolimus; Mycophenolic Acid; Tacrolimus
• Other Study ID Numbers: PMR-EC-1212; 2010-019639-37 (EudraCT Number)

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 study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• 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