12 Month Athena Study: Everolimus vs. Standard Regimen in de Novo Kidney Transplant Patients (ATHENA)

12 Month, Multi-center, Open-label, Prospective, Randomized, Parallel Group Study Investigating a Standard Regimen in de Novo Kidney Transplant Patients Versus a Certican® Based Regimen Either in Combination With Cyclosporin A or Tacrolimus

This study was designed to evaluate the renal function comparing Certican based immunosuppressive regimens with two different CNIs (Tacrolimus or Cyclosporin A) versus a standard treatment with Mycophenolic Acid and Tacrolimus in de novo renal transplant recipients.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation; Renal Transplantation
• Intervention / Treatment: Drug: Everolimus; Drug: Tacrolimus; Drug: Enteric Coated Mycophenolate Sodium (EC-MPS); Drug: Mycophenolate mofetil (MMF); Drug: Corticosteroids; Drug: Simulect; Drug: Cyclosporin A

• Study Type: Interventional
• Enrollment (Actual): 612
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Bordeaux Cedex, France, 33076
    • Novartis Investigative Site
  • Brest, France, 29200
    • Novartis Investigative Site
  • Creteil, France, 94010
    • Novartis Investigative Site
  • Dijon, France, 21079
    • Novartis Investigative Site
  • Lille Cedex, France, 59037
    • Novartis Investigative Site
  • Lyon, France, 69437
    • Novartis Investigative Site
  • Nantes, France, 44035
    • Novartis Investigative Site
  • Paris, France, 75970
    • Novartis Investigative Site
  • Poitiers, France, 86000
    • Novartis Investigative Site
  • St Priest en Jarez Cedex, France, 42277
    • Novartis Investigative Site
  • Strasbourg, France, 67091
    • Novartis Investigative Site
  • Toulouse Cedex 4, France, 31054
    • Novartis Investigative Site
• Germany
  • Aachen, Germany, 52074
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Bochum, Germany, 44892
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Erlangen, Germany, 91052
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Kiel, Germany, 24105
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • Tübingen, Germany, 72076
    • Novartis Investigative Site

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:

• Patient who had received a primary or secondary kidney transplant
• Patients who were willing and from whom written informed consent was obtained
• kidney allograft with a cold ischemia time (CIT) < 30 hours
• negative pregnancy test prior to study enrollment

Exclusion Criteria:

--Multi-organ recipients

• former Graft loss due to immunological reasons
• Patients who received a kidney from a non-heart beating donor
• A-B-0 incompatible transplants
• a current Panel Reactive Antibody (PRA) level of > 20%
• existing antibodies against the HLA-type of the receiving transplant
• a known hypersensitivity/contraindication to any of the immunosuppressants
• Use of other investigational drugs
• Patients with thrombocytopenia (platelets < 100,000/mm³), with an absolute neutrophil count of < 2,000/mm³ or leucopenia (leucocytes < 3,000/mm³), or hemoglobin < 8 g/dL
• significant mental illness
• history of malignancy during the last five years
• HIV positive
• uncontrolled hypercholesterolemia or hypertriglyceridemia
• drug or alcohol abuse
• pregnant or breast feeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: TAC+MPA	Drug: Tacrolimus; Capsules: 0.5 mg, 1 mg or 5 mg. Dosing schedule: transplant to month 2: 4-8ng/ml, month 3 to month 12 3-5 ng/ml according to standard blood levels; Drug: Enteric Coated Mycophenolate Sodium (EC-MPS); Tablets: 180 mg or 360 mg. Dosing: duration of study 360 mg bid and no less than 360 mg daily dose; Drug: Mycophenolate mofetil (MMF); Capsules: 250 or 500 mg. Dosing: duration of study 500 mg bid and no less than 500 mg total daily dose; Drug: Corticosteroids; A minimum dose of 5 mg prednisolon or equivalent; Drug: Simulect; Lyophilisate in vials with ampoules of sterile water for injection (5 mL), one vial containing 20 mg lyophilisate given intravenously on the day of transplantation and on day four post-transplantation.; Other Names: Basiliximab
EXPERIMENTAL: TAC+Certican	Drug: Everolimus; Other Names: Certican; Drug: Tacrolimus; Capsules: 0.5 mg, 1 mg or 5 mg. Dosing schedule: transplant to month 2: 4-8ng/ml, month 3 to month 12 3-5 ng/ml according to standard blood levels; Drug: Corticosteroids; A minimum dose of 5 mg prednisolon or equivalent; Drug: Simulect; Lyophilisate in vials with ampoules of sterile water for injection (5 mL), one vial containing 20 mg lyophilisate given intravenously on the day of transplantation and on day four post-transplantation.; Other Names: Basiliximab
EXPERIMENTAL: CycA+Certican	Drug: Everolimus; Other Names: Certican; Drug: Corticosteroids; A minimum dose of 5 mg prednisolon or equivalent; Drug: Simulect; Lyophilisate in vials with ampoules of sterile water for injection (5 mL), one vial containing 20 mg lyophilisate given intravenously on the day of transplantation and on day four post-transplantation.; Other Names: Basiliximab; Drug: Cyclosporin A; Capsules: 10 mg, 25 mg, 50 mg or 100 mg. Transplantation to month 2: 75 - 125 ng/ml, month 3 to month 12: 50 - 100 ng/ml

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glomular Filtration Rate (GFR) mL/Min Via Nankivell Method at Month 12 - Standard Regimen vs Certican Regimens	To demonstrate non-inferiority in renal function assessed by glomerular filtration rate (Nankivell formula) in at least one of the Certican® treatment regimens compared to the standard regimen group at month 12 post-transplantation in renal transplant patients. Nankivell formula: GFR = 6.7/Scr + BW/4 - Surea/2 - 100/(height)² + C where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kg, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The eGFR is expressed in mL/min per 1.73m². If a patient was on dialysis at the time of urea or creatinine assessment, the eGFR was set to 0. Analysis set = per protocol set	One year post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Composite Treatment Failure Endpoints - Difference Between Groups at Month 12	Combined endpoint included: biopsy proven acute rejection (BPAR) defined as a rejection which was acute and proven by biopsy, graft loss (GL) defined as: allograft was presumed to be lost on the day the patient starts dialysis and not able to be removed from dialysis or death. Patients who prematurely discontinued the study: if the patient did not suffer from an event before discontinuation and reason was not related to efficacy, the patient was assessed as having had no event, otherwise the patient was assessed as having had an event. Full analysis set (FAS)	Month 12 post transplant
Glomular Filtration Rate (GFR) Via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Method at Month 12 Post Transplant	Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method = GFR=141 x min(Scr/κ, 1)α x max(Scr/κ, 1)1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black] where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is 0.329 for females and 0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model	Month 12 post transplant
Glomular Filtration Rate (GFR) mL/Min Via Cockcroft- Gault Method at Month 12 Post Transplant	Cockcroft-Gault formula: For men: GFR= ((140-age) × body weight in kg)∕(72 x serum creatinine in mg∕dl)For women: GFR= (0.85×(140-age) × body weight in kg)∕(72 x serum creatinine in mg/dl), ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model	Month 12 post transplant
Glomular Filtration Rate (GFR) Via Modification of Diet in Renal Disease (MDRD) Method at Month 12 Post Transplant	Modification of Diet in Renal Disease (MDRD) = For men: GFR = 170 x (serum creatinine -0,999) x (age-0,176) x (urea nitrogen -0,17) x (albumin0,318) For women: GFR = 170 x (serum creatinine -0,999) x (age-0,176) x (urea nitrogen -0,17) x albumin0,318) x 0.762 with urea nitrogen = urea / 2.144. last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model	Month 12 post transplant
Percentage of Participants With Treatment Failure Endpoints at Month 12	Treatment failure endpoints: biopsy proven acute rejection (BPAR) defined as a rejection which was acute and proven by biopsy, graft loss (GL) defined as: allograft was presumed to be lost on the day the patient starts dialysis and not able to be removed from dialysis or death. Patients who prematurely discontinued the study: if the patient did not suffer from an event before discontinuation and reason was not related to efficacy, the patient was assessed as having had no event, otherwise the patient was assessed as having had an event. Full analysis set (FAS)	Month 12 post transplant
Percent of Participants With Delayed Graft Function and Slow Graft Function	Delayed graft function (DGF) was defined as the need for dialysis within the first 7 days post-transplantation, excluding the first post-transplantation day. Slow graft function (SGF) was defined as a serum creatinine >3.0 mg/dL at Day 5 post-transplantation. Full analysis set	Post transplant to month 12
Percent of Participants With Delayed Graft Function by Day	Delayed graft function (DGF) was defined as the need for dialysis within the first 7 days post-transplantation, excluding the first post-transplantation day.	Post transplant up to day 7
Percent of Participants With Viral Infections	Viral infections for BKV Virus Humane Polyomavirus 1 and Cytomegalovirus	Post transplant to month 12
Percent of Participants With Wound Healing Complications During Study	Information collected to report wound healing process which included percentage of participants with complications, fluid collections detected and occurrence of lymphoceles	Post transplant until individual reporting
Duration of Wound Healing	A wound will be considered healed if all the suture material and staples are removed and the wound is intact. Number of participants is based on all patients of the respective treatment group in the safety set, excluding patients with no answer (unknown).	Post transplant until individual reporting

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Sommerer C, Suwelack B, Dragun D, Schenker P, Hauser IA, Nashan B, Thaiss F. Design and rationale of the ATHENA study--A 12-month, multicentre, prospective study evaluating the outcomes of a de novo everolimus-based regimen in combination with reduced cyclosporine or tacrolimus versus a standard regimen in kidney transplant patients: study protocol for a randomised controlled trial. Trials. 2016 Feb 17;17:92. doi: 10.1186/s13063-016-1220-9.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 27, 2012
• Primary Completion (ACTUAL): March 23, 2016
• Study Completion (ACTUAL): March 23, 2016

Study Registration Dates

• First Submitted: April 18, 2013
• First Submitted That Met QC Criteria: April 26, 2013
• First Posted (ESTIMATE): April 30, 2013

Study Record Updates

• Last Update Posted (ACTUAL): May 1, 2017
• Last Update Submitted That Met QC Criteria: March 21, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Rejection; Transplant; Kidney Transplant; Renal transplant; Rejection,allograf; Xenograft rejection; Host vs graft disease
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Everolimus; Basiliximab; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CRAD001ADE44; 2011-005238-21 (EUDRACT_NUMBER)