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

Chronic Renal Failure Clinical Trial

Official title:

Efficacy and Safety of Certican® (Everolimus) in Combination With Myfortic® (EC-MPS, Enteric-coated Mycophenolate Sodium) After Early CNI Elimination Versus Myfortic® in Combination With Prograf® in Renal Transplant Recipients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00965094
• Other study ID #: CRAD001AIL03
• Status: Completed
• Phase: Phase 4
• First received: August 24, 2009
• Last updated: August 14, 2014
• Start date: December 2009
• Est. completion date: June 2013

Study information

• Verified date: August 2014
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: Israel: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: June 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion criteria:

• 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.

Exclusion criteria:

• 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)

• Presence of a clinically significant infection requiring continued therapy, severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus that in the opinion of the investigator would interfere with the appropriate conduct of the study

• Evidence of drug or alcohol abuse

• Patients receiving drugs known to interact with Tacrolimus and/or everolimus according to the list provided in Appendix 3 to this protocol.

• Other protocol-defined inclusion/exclusion criteria may apply

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Renal Failure
• Kidney Failure, Chronic

Intervention

Drug:
• Everolimus
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)
• Tacrolimus (FK506)
Capsules 0.5 mg, 1 mg. Dosing according to blood level.
• Basiliximab
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.
• Enteric Coated Mycophenolate Sodium (EC-MPS)
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)
• Corticosteroids
Used according to Israeli standards. A minimum dose of 5mg [prednisone, or equivalent, was used throughout the study period.

Locations

Country	Name	City	State
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Tel-Aviv

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

Israel, 

References & 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Assessment of GFR by the Cockcroft-Gault Method (LOCF)	the GFR was also calculated using the Cockcroft-Gault method (Cockcroft and Gault 1976) and the Modification of Diet in Renal Disease (MDRD) method (Levey et al., 1999, Rodrigo et al., 2003; Pierrat et al., 2003).Cockcroft-Gault formula For men: GFR= (140-Age)X Body Weight[kg]/72X Serum Creatinine[mg/dl] For women: GFR= 0,85x(140-Age) x Body Weight[kg]/72x Serum Creatinine [mg/dl] The Last Observation Carried Forward (LOCF) imputation technique was used for this analysis.	9 months	Yes
Secondary	Participants Who Had Occurrence of Biopsy Proven Acute Rejection, Graft Loss or Death.	Biopsy-proven acute rejection was defined as a biopsy gradeed IA, IB, IIA, IIB, or III. The allograft was presumed to be lost if the patient started dialysis and was not able to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was the day of graft loss.	9 months	Yes
Secondary	Participants Who Had Occurrence of Treatment Failure.	Treatment failure was defined as a composite endpoint of biopsy-proven acute rejection, graft loss, death, loss to follow up, discontinuation due to lack of efficacy or toxicity or conversion to another regimen.	9 months	No
Secondary	Change in Renal Function (Creatinine Slope)	X(slope)=(1/value of creatinine).	3 months, 5 months, 7 months, 9 months	Yes