Concentration Controlled Everolimus With Reduced Dose Cyclosporine Versus Mycophenolate Mofetil With Standard Dose Cyclosporine in de Novo Renal Transplant Adult Recipients Treated With Basiliximab and Corticosteroids

NCT00658320 | Completed Phase 3 Results

• 1 other identifier: CRAD001A1202
• Study Type: interventional
• Target: 122
• Locations: 1 country
• Sites: 1

Brief Summary

The 12 Month Core Study (CRAD001A1202) was designed to evaluate the efficacy and safety comparing concentration-controlled everolimus (1.5 mg/day starting dose) with reduced dose cyclosporine and corticosteroids versus 2 g/day mycophenolate mofetil (MMF) with standard dose cyclosporine and corticosteroids in de novo renal transplant recipients. Extension Study (CRAD001A1202E1): Until 24 months after renal transplantation, the study was designed to evaluate the long-term safety and efficacy comparing concentration-controlled everolimus with reduced dose cyclosporine (Neoral®) and corticosteroids versus mycophenolate mofetil with standard dose Neoral® and corticosteroids in de novo renal transplant recipients. Beyond 24 months after renal transplantation, the study was designed to provide everolimus treatment for patients in everolimus group until everolimus is approved and marketed in Japan.

Conditions

Kidney Transplantation

Keywords

Renal transplantation; everolimus; mycophenolate mofetil; cyclosporine; corticosteroid; basiliximab; Banff diagnosis; Acute rejection; Therapeutic drug monitoring (TDM); de novo renal transplant recipient

Outcome Measures

Primary Outcomes (3)

• Core Study: Number of Patients With Composite Efficacy Endpoint

  The composite efficacy endpoint consisted of treated biopsy proven acute rejection (BPAR) episodes, graft loss, death or loss to follow-up. A treated BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III and which was treated with anti-rejection therapy. The allograft was presumed to be lost on the day the patient starts dialysis and was not able to stop dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was considered as the day of graft loss. For the individual components (including loss of follow-up)of the composite endpoint, patients are counted for the first event to occur.

  12 months

• Extension Study: Renal Function Measured by Calculated Glomerular Filtration Rate (cGFR) Using the Modification of Diet in Renal Disease (MDRD) Formula

  Renal function was assessed by glomerular filtration rate (GFR) using the MDRD formula: GFR \[mL/min/1.73m2\] = 186.3\*(C-1.154)\*(A-0.203)\*G\*R C is the serum concentration of creatinine \[mg/dL\] A is age \[years\] G = 0.742 when gender is female, otherwise G=1 R = 1.21 when race is black, otherwise R=1 Loss to follow up (in In Primary Core Outcome Measure) is composite efficacy failure and contains incidence of treated BPAR, graft loss, death or loss to follow-up

  Month 24

• Extension Study: Renal Function Measured by Calculated Glomerular Filtration Rate (cGFR) Using the Modification of Diet in Renal Disease (MDRD) Formula

  Renal function was assessed by glomerular filtration rate (GFR) using the MDRD formula: GFR \[mL/min/1.73m2\] = 186.3\*(C-1.154)\*(A-0.203)\*G\*R C is the serum concentration of creatinine \[mg/dL\] A is age \[years\] G = 0.742 when gender is female, otherwise G=1 R = 1.21 when race is black, otherwise R=1

  Month 48

Secondary Outcomes (7)

• Core Study: Number Participants With Combined Graft Loss, Death or Loss to Follow-up

  12 months

• Core Study: Renal Function Measured by Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula

  Month 12

• Extension Study: Number of Participants With Combined Efficacy Endpoint: Graft Loss, Death, Loss to Follow-up and/or Treated Biopsy Proven Acute Rejection (BPAR)

  24 Months

• Extension Study: Renal Function Measured by Calculated Glomerular Filtration Rate (GFR) Using the Nankivell Formula

  Month 24, Month 48

• Extension Study: Number of Participants With Adverse Events and Serious Adverse Events

  24 Months

Study Arms (2)

Everolimus + Reduced dose of cyclosporine

EXPERIMENTAL

An initial everolimus dose of 0.75 mg orally twice daily (1.5 mg/day) was administered 24-36 hours from reperfusion after transplantation and dose adjustments based on everolimus trough level (target trough level 3-8 ng/mL). Reduced dose of cyclosporine was initiated either pre-transplantation or within 24 hours after transplantation following the local regimen. Patients were treated with antibody induction therapy using 20 mg basiliximab two hours prior to transplant and 20 mg basiliximab 4 days post transplant or according to local practice. Corticosteroids were administered according to local practice. Patients were treated for 12 months in the core study and 12 months in the extension study. Everolimus was available after 24 months for compassionate use.

Drug: Everolimus; Drug: Basiliximab; Drug: Cyclosporine A; Drug: Corticosteroid

Mycophenolate mofetil (MMF) + Standard dose of cyclosporine

ACTIVE COMPARATOR

Patients were treated with 1 gram twice a day (2 grams/day) of Mycophenolate mofetil (MMF) and standard dose of cyclosporine for 12 months post renal transplant. Patients were treated with antibody induction therapy using 20 mg basiliximab two hours prior to transplant and 20 mg basiliximab 4 days post transplant or according to local practice. Corticosteroids were administered according to local practice. Patients were treated for 12 months in the core study and 12 months in the extension study.

Drug: Mycophenolate mofetil (MMF); Drug: Basiliximab; Drug: Cyclosporine A; Drug: Corticosteroid

Interventions

Everolimus DRUG

0.75 mg twice daily, trough level adjusting between 3 and 8 ng/ml.

Also known as: Certican

Everolimus + Reduced dose of cyclosporine

Mycophenolate mofetil (MMF) DRUG

The initial dose of 2 gm/day Mycophenolate mofetil was started within 24-36 hours from reperfusion after transplantation. MMF was administered daily for 12 months in the core study and 12 months in the extension study.

Also known as: MMF

Mycophenolate mofetil (MMF) + Standard dose of cyclosporine

Basiliximab DRUG

Patients received first dose of basiliximab (20 mg) 2 hours prior to transplantation and 20 mg at Day 4 or according to local practice

Everolimus + Reduced dose of cyclosporine; Mycophenolate mofetil (MMF) + Standard dose of cyclosporine

Cyclosporine A DRUG

The cyclosporine was initiated either pre-transplant or within 24 hours after transplantation following local regime. Standard dose of cyclosporine was administered with MMF. The Reduced dose of cyclosporine was administered with everolimus.

Also known as: Neoral®

Everolimus + Reduced dose of cyclosporine; Mycophenolate mofetil (MMF) + Standard dose of cyclosporine

Corticosteroid DRUG

Corticosteroid was administered according to local practice during the trial but at a dose not less than 5mg per day for 12 months of the study

Everolimus + Reduced dose of cyclosporine; Mycophenolate mofetil (MMF) + Standard dose of cyclosporine

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female de novo renal transplant recipients between 18 and 65 years of age
• Patients who are receiving a primary cadaveric donor or non-human leukocyte antigen (non-HLA) identical living donor kidney transplant
• Patients who have given written informed consent to participate in the study
• Females capable of becoming pregnant must have a negative pregnancy test prior to randomization.

You may not qualify if:

• Patients with no evidence of graft function within 24 hours of transplantation are excluded
• Recipients of dual kidney transplants
• Patients who are recipients of multiple solid organ or tissue transplants, or have previously received an organ or tissue transplant.
• Recipients of kidneys from HLA-identical living related donors
• Patients who are recipients of ABO incompatible transplants or T cell cross match positive transplant. Although Panel Reactive Antibodies (PRA) test is not mandatory, patients whose most recent anti-HLA Class I PRA \>20% By a CDC-(Complement dependent cytotoxicity) based assay or \>50% by a Flow Cytometry or ELISA (Enzyme linked immunosorbent assay) -based assay
• Patients who have tested positive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Hepatitis B surface antigen. Laboratory results obtained within 6 months prior to randomization are acceptable, otherwise these tests should be performed within two weeks prior to randomization.
• Recipients of organs from donors who test positive for Hepatitis B surface antigen, HCV or HIV are excluded
• Donor organ with a cold ischemia time \>24 hours
• Donor age greater than 65 years
• Patients with platelet count \<100,000/mm at baseline before transplantation
• Patients with an absolute neutrophil count of \< 1,500/mm³ or white blood cell count of \< 4,500/mm³ at baseline before transplantation
• Patients who have severe hypercholesterolemia (\>350 mg/dL; \>9 mmol/L) or hypertriglyceridemia (\>500 mg/dL; \>8.5 mmol/L). Patients with controlled hyperlipidemia are acceptable
• Patients who have an abnormal liver profile such as alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alkaline phosphatase (ALP) or total bilirubin \>3 times the upper limit of normal (ULN)
• Patients with a known hypersensitivity to either of the study drugs or their class, or to any of the excipients
• Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450

Sponsors & Collaborators

• Novartis: lead

Study Sites (1)

Novartis Pharma K.K., Japan

Tokyo, 106-8618, Japan

Location

Related Publications (1)

• Takahashi K, Uchida K, Yoshimura N, Takahara S, Teraoka S, Teshima R, Cornu-Artis C, Kobayashi E. Efficacy and safety of concentration-controlled everolimus with reduced-dose cyclosporine in Japanese de novo renal transplant patients: 12-month results. Transplant Res. 2013 Jul 16;2(1):14. doi: 10.1186/2047-1440-2-14.

  PMID: 23866828 DERIVED

MeSH Terms

Interventions

Everolimus; Mycophenolic Acid; Basiliximab; Cyclosporine; Adrenal Cortex Hormones

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis

  Novartis

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2008
• First Posted: April 15, 2008
• Study Start: February 1, 2008
• Primary Completion: August 1, 2010
• Study Completion: May 1, 2012
• Last Updated: June 21, 2013
• Results First Posted: September 14, 2011

Record last verified: 2013-05

Locations

JP (1)