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

• ClinicalTrials.gov Identifier: NCT01843348
• Recruitment Status: Completed
• First Posted: April 30, 2013
• Results First Posted: May 1, 2017
• Last Update Posted: May 1, 2017
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Kidney Transplantation; Renal Transplantation	Drug: Everolimus; Drug: Tacrolimus; Drug: Cyclosporin A; Drug: Enteric Coated Mycophenolate Sodium (EC-MPS); Drug: Mycophenolate mofetil (MMF); Drug: Corticosteroids; Drug: Simulect	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 612 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 27, 2012
• Actual Primary Completion Date: March 23, 2016
• Actual Study Completion Date: March 23, 2016

Arms and Interventions

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 Name: Basiliximab
Experimental: TAC+Certican	Drug: Everolimus; Other Name: 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 Name: Basiliximab
Experimental: CycA+Certican	Drug: Everolimus; Other Name: Certican; 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; 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 Name: Basiliximab

Outcome Measures

Primary Outcome Measures :

1. Glomular Filtration Rate (GFR) mL/Min Via Nankivell Method at Month 12 - Standard Regimen vs Certican Regimens [ Time Frame: One year post transplant ]

   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

Secondary Outcome Measures :

1. Percentage of Participants With Composite Treatment Failure Endpoints - Difference Between Groups at Month 12 [ Time Frame: Month 12 post transplant ]
   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)
2. Glomular Filtration Rate (GFR) Via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Method at Month 12 Post Transplant [ Time Frame: 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
3. Glomular Filtration Rate (GFR) mL/Min Via Cockcroft- Gault Method at Month 12 Post Transplant [ Time Frame: 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
4. Glomular Filtration Rate (GFR) Via Modification of Diet in Renal Disease (MDRD) Method at Month 12 Post Transplant [ Time Frame: 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
5. Percentage of Participants With Treatment Failure Endpoints at Month 12 [ Time Frame: Month 12 post transplant ]
   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)
6. Percent of Participants With Delayed Graft Function and Slow Graft Function [ Time Frame: Post transplant to month 12 ]
   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
7. Percent of Participants With Delayed Graft Function by Day [ Time Frame: Post transplant up to day 7 ]
   Delayed graft function (DGF) was defined as the need for dialysis within the first 7 days post-transplantation, excluding the first post-transplantation day.
8. Percent of Participants With Viral Infections [ Time Frame: Post transplant to month 12 ]
   Viral infections for BKV Virus Humane Polyomavirus 1 and Cytomegalovirus
9. Percent of Participants With Wound Healing Complications During Study [ Time Frame: Post transplant until individual reporting ]
   Information collected to report wound healing process which included percentage of participants with complications, fluid collections detected and occurrence of lymphoceles
10. Duration of Wound Healing [ Time Frame: Post transplant until individual reporting ]
    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).

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

France

Novartis Investigative Site

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

Germany

Novartis Investigative Site

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

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01843348
• Other Study ID Numbers: CRAD001ADE44; 2011-005238-21 ( EudraCT Number )
• First Posted: April 30, 2013
• Results First Posted: May 1, 2017
• Last Update Posted: May 1, 2017
• Last Verified: March 2017

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Transplant; Renal transplant; Rejection,allograf; Rejection; Xenograft rejection; Host vs graft disease; Kidney Transplant

Additional relevant MeSH terms:

Cyclosporine; Mycophenolic Acid; Everolimus; Tacrolimus; Cyclosporins; Basiliximab; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Antirheumatic Agents; Antineoplastic Agents; Antibiotics, Antineoplastic; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents