Efficacy and Safety of Everolimus+EC-MPS After Early CNI Elimination vs EC-MPS +Tacrolimus in Renal Transplant Recipients

NCT00965094 | Completed Phase 4 Results

• 1 other identifier: CRAD001AIL03
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 3

Brief Summary

The primary objective of this trial is to show non-inferiority of a CNI-free regimen with respect to the renal function at Month 9 post Tx assessed by glomerular filtration rate - Nankivell method - as compared to the standard CNI-based regimen in de novo renal transplant patients.

Conditions

Chronic Renal Failure

Outcome Measures

Primary Outcomes (1)

• Renal Function Assessed as Glomerula Filtration Rate (GFR) - Nankivell Method - 9 Months After Renal Transplantation (LOCF)

  The glomerular filtration rate (GFR) is the best clinical estimate of renal function in health and disease, and correlates well with the clinical severity of renal function disturbances. The GFR, calculated according to the Nankivell formula, was used as the primary outcome measure in this study. This equation has been validated in renal transplant patients against the true GFR measured by a radionuclide method and has been confirmed as a very accurate method to calculate the GFR in this specific population (Gaspari et al., 2004)GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C Scr = serum creatinine concentration expressed in mmol/L. BW = body weight in kg, Surea = serum urea in mmol/L and Height is expressed in meters.The Last Observation Carried Forward (LOCF) imputation technique was used for this analysis.

  9 months

Secondary Outcomes (4)

• Assessment of GFR by the Cockcroft-Gault Method (LOCF)

  9 months

• Participants Who Had Occurrence of Biopsy Proven Acute Rejection, Graft Loss or Death.

  9 months

• Participants Who Had Occurrence of Treatment Failure.

  9 months

• Change in Renal Function (Creatinine Slope)

  3 months, 5 months, 7 months, 9 months

Study Arms (2)

Everolimus

EXPERIMENTAL

At BL1, all study patients received induction therapy with basiliximab (Simulect®; 2x20mg on day 0 - 2 hours prior to transplantation, and on day 4 after transplantation) and commenced an immunosuppressive regimen consisting of MPA (Myfortic®; target dose: 1440 mg/day, which was also the maximum daily dose) + tacrolimus (Prograf®; based on C0-h levels; Table 9-2) and with corticosteroids. AT BL2 \[Month 3 (+1 week) after transplantation\], eligible patients were randomized, using living and cadaveric donation as stratum. Patients were switched to the CNI-free regimen. Everolimus was added to the patients immunosuppressive regimen and tacrolimus was removed successively.

Drug: Everolimus; Drug: Basiliximab; Drug: Enteric Coated Mycophenolate Sodium (EC-MPS); Drug: Corticosteroids

Reference Therapy

ACTIVE COMPARATOR

At BL1, all study patients received induction therapy with basiliximab (Simulect®; 2x20mg on day 0 - 2 hours prior to transplantation, and on day 4 after transplantation) and commenced an immunosuppressive regimen consisting of MPA (Myfortic®; target dose: 1440 mg/day, which was also the maximum daily dose) + tacrolimus (Prograf®; based on C0-h levels; Table 9-2) and with corticosteroids. AT BL2 \[Month 3 (+1 week) after transplantation\], eligible patients were randomized, using living and cadaveric donation as stratum. Patients continued on the prior immunosuppressive regimen consisting of MPA + tacrolimus with corticosteroids.

Drug: Tacrolimus (FK506); Drug: Basiliximab; Drug: Enteric Coated Mycophenolate Sodium (EC-MPS); Drug: Corticosteroids

Interventions

Everolimus DRUG

One tablet containing 0.25, 0.5mg or 0.75 mg. Initially 2 mg/day. Afterwards based on blood level (target 6-10 ng/mL)

Also known as: Certican

Everolimus

Tacrolimus (FK506) DRUG

Capsules 0.5 mg, 1 mg. Dosing according to blood level.

Also known as: Prograf

Reference Therapy

Basiliximab DRUG

One vial containing 20 mg lyophilisate. 2 x 20 mg \[day 0 (2 hrs prior to Tx) and day 4 post Tx\] to be applied as 10 sec. bolus injection, i.v.

Also known as: Simulect

Everolimus; Reference Therapy

Enteric Coated Mycophenolate Sodium (EC-MPS) DRUG

One tablet containing 180 mg or 360 mg. 1440 mg/day (2x720 mg). If tolerated, dose reduction due to side effectis were possible (min. dose at BL@: 720 mg/day)

Also known as: Myfortic

Everolimus; Reference Therapy

Corticosteroids DRUG

Used according to Israeli standards. A minimum dose of 5mg \[prednisone, or equivalent, was used throughout the study period.

Everolimus; Reference Therapy

Eligibility Criteria

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

You may qualify if:

• Recipients of de novo cadaveric, living unrelated or living related kidney transplants
• Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at screening, and are required to practice an approved method of birth control for the duration of the study and for a period of 6 weeks following discontinuation of study medication, even where there has been a history of infertility.
• Patients who are willing and able to participate in the study and from whom written informed consent has been obtained.

You may not qualify if:

• More than one previous renal transplantation
• Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any other organ, different from kidney
• Donor age: \< 5 years or \> 65 years
• Graft loss due to immunological reasons in the first year after transplantation (in case of secondary transplantation)
• Patients who had received an investigational drug within 4 weeks of the baseline period
• Patients who are recipients of A-B-O incompatible transplants or T cell cross-match positive transplants
• Patients with already existing antibodies against the HLA-type of the receiving transplant
• Patients with any known hypersensitivity to Simulect®, Certican®, mycophenolic acid, Prograf®, other drugs similar to Certican® (e.g., macrolides), or other components of the formulations.
• Patients who have received an investigational immunosuppressive drug within four weeks prior to study entry (Baseline visit 1)
• Patients with thrombocytopenia (platelets \< 75,000/mm³), or an absolute neutrophil count of \< 1,500/mm³ or leucopenia (leucocytes \< 2,500/mm³), or hemoglobin \< 6 g/dL
• Patients with preexisting lung disease (alveolitis, fibrosis) Patients with symptoms of significant somatic or mental illness. Inability to cooperate or communicate with the investigator, who are unlikely to comply with the study requirements, or who are unable to give informed consent
• Patients with a history of malignancy during the last five years, except squamous or basal cell carcinoma of the skin
• Patients who are HIV positive or Hepatitis B surface antigen positive or Hepatitis C virus positive. Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C are excluded.
• Evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin \> 3 times UNL)
• Females of childbearing potential who are planning to become pregnant, who are pregnant or lactating, and/or who are unwilling to use effective means of contraception (see also section 8.2)

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (3)

Novartis Investigative Site

Haifa, 31096, Israel

Location

Novartis Investigative Site

Petah Tikva, 49100, Israel

Location

Novartis Investigative Site

Tel Aviv, 64239, Israel

Location

Related Publications (1)

• Bemelman FJ, de Maar EF, Press RR, van Kan HJ, ten Berge IJ, Homan van der Heide JJ, de Fijter HW. Minimization of maintenance immunosuppression early after renal transplantation: an interim analysis. Transplantation. 2009 Aug 15;88(3):421-8. doi: 10.1097/TP.0b013e3181af1df6.

  PMID: 19667948 BACKGROUND

MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

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

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 24, 2009
• First Posted: August 25, 2009
• Study Start: December 1, 2009
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: August 15, 2014
• Results First Posted: August 15, 2014

Record last verified: 2014-08

Locations

IL (3)