Once-a-day Regimen With Everolimus, Low Dose Cyclosporine and Steroids in Comparison With Steroid Withdrawal or Twice a Day Regimen With Everolimus, Low Dose Cyclosporine and Steroids.

NCT ID: NCT01023815

Last Updated: 2016-07-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 330 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-04-30
• Study Completion Date: 2012-07-31

Brief Summary

This study will compare the following immunosuppressive regimens in recipients of kidney transplantation: A) everolimus, cyclosporine and steroids given once-a-day; B) everolimus and cyclosporine given twice a day with steroid withdrawal; C) everolimus, cyclosporine given twice a day and continuous steroids. The purpose of this study is to evaluate regimens A and B in comparison with the control group (group C) for efficacy, using as main endpoint the treatment failure rate, a composite endpoint including death, graft loss, BPAR and lost to follow-up between randomization and Month 12.

Conditions

de Novo Kidney Transplant Recipients; Renal Transplantation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Group A -Once-a-day regimen

Everolimus: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole daily dose of everolimus was taken in the morning, at the same time of the CsA and steroid dosing. At the Rand+1W visit, the everolimus dose was adjusted to reach and maintain everolimus blood levels between 5 and 8 ng/mL until end of Month 12.

Cyclosporine: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole cyclosporine daily dose was taken in the morning. The dose was then adjusted to maintain C2 levels between 350 and 700 ng/mL.

Prednisone: In patients randomized to Group A before Amendment 1 approval, the dose of prednisone was kept stable at 5 mg/day in the morning.

Group Type: EXPERIMENTAL

everolimus

Intervention Type: DRUG

Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.

cyclosporine

Intervention Type: DRUG

Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant.

Prednison (continuous steroids)

Intervention Type: DRUG

continuous steroids

Group B - Steroid Withdrawal group

Everolimus: after randomization the everolimus dose was adjusted, if necessary, to maintain a C0 within 6-10 ng/mL until M12.

Cyclosporine:after randomization the cyclosporine dose was adjusted to maintain CsA C2 levels within 300-500 ng/mL until M12.

Prednisone: starting from Visit 5 (day 90 ± 28 days), oral prednisone was tapered until complete stop. It was recommended to taper prednisone by 1 mg/week until complete stop in 5 to 6 weeks.

Group Type: EXPERIMENTAL

everolimus

Intervention Type: DRUG

Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.

cyclosporine

Intervention Type: DRUG

Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant.

Prednison (continuous steroids)

Intervention Type: DRUG

continuous steroids

Group C - Standard twice-a-day group

Everolimus: after randomization the everolimus dose was adjusted, if necessary, in order to maintain a C0 within 6-10 ng/mL until M12.

Cyclosporine: after randomization the cyclosporine dose was gradually adjusted to reach and maintain C2 blood levels of 200-450 ng/mL between Month 6 and Month 12.

Prednisone: the dose of prednisone was kept stable at 5 mg/day in the morning.

Group Type: ACTIVE_COMPARATOR

everolimus

Intervention Type: DRUG

Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.

cyclosporine

Intervention Type: DRUG

Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant.

Prednison (continuous steroids)

Intervention Type: DRUG

continuous steroids

Not Randomized Population (NRP)

NRP defined in whom a renal transplantation was performed, received at least one dose of study drug (everolimus) but who did not qualify for randomization at Visit 5, Day 90. This group was addressed as "not randomized patients" (NRP) and described with respect to baseline characteristics, treatment and outcome variables.

Group Type: EXPERIMENTAL

everolimus

Intervention Type: DRUG

Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.

Interventions

everolimus

Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.

Intervention Type: DRUG

cyclosporine

Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant.

Intervention Type: DRUG

Prednison (continuous steroids)

continuous steroids

Intervention Type: DRUG

Other Intervention Names

Certican®); CsA, Sandimmun® Neoral®

Eligibility Criteria

Inclusion Criteria

• recipients of 1st or 2nd single kidney transplant
• donor age >14 years
• females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at Baseline (Visit 2), and are required to practice an approved method of birth control for the duration of the study and for a period of 2 months following discontinuation of study medication
• patientswho are willing and able to participate in the study and from whom written informed consent has been obtained

Exclusion Criteria

• recipients of kidney-pancreas transplant, double kidney or any other transplant
• recipients of a 2nd kidney transplant who lost the 1st for immunological reasons
• focal segmental glomerulosclerosis (FSGS), primary oxaluria or other diseases (as cause of end stage renal failure - ESRF) at high risk of rapid recurrence or requiring continuous corticosteroid treatment
• recipients of A-B-O incompatible transplants
• historical or current peak PRA of >25% (current = 3 months)
• patients with already existing antibodies against the donor
• thrombocytopenia (platelets <75,000/mm³), absolute neutrophil count of <1,500/mm³, leucopenia (leucocytes <2,500/mm³), or hemoglobin <6 g/dL
• symptoms of significant somatic or mental illness. Inability to cooperate or communicate with the investigator, or to comply with the study requirements, or to give informed consent
• history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
• patients who are HIV positive or Hepatitis B surface antigen positive (HbsAg); HCV positive patients receiving interferon and/or ribavirin
• evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin >3 times UNL)
• evidence of drug or alcohol abuse
• body mass index (BMI) >35
• patients who need to be treated with drugs known to strongly interact with CsA and/or everolimus (as detailed in Appendix 2 of the protocol) should be excluded, if according the investigator this interferes with the objectives of the study
• women of child-bearing potential, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method
• pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>5 mIU/mL)
• use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
• history of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
• patients with severe active infections or any other medical condition(s) that in the view of the investigator prohibits participation in the study (specify as required)

• graft not perfused or with thrombosis of the main vessels, according to angioscintigraphy or echocolordoppler within 48 hours after the end of surgical procedure

• unsatisfactory renal function (CrCl according Cockcroft and Gault<40 mL/min)
• proteinuria ≥0.8 g/24 hrs
• steroid-resistant, humoral, moderate/severe (BANFF grade ≥II) biopsy proven acute rejections
• multiple (2 or more) biopsy proven or treated acute rejections or acute rejections leading to relevant loss of renal function
• acute rejection or impairment of renal function (increase of serum creatinine>30%) in the month preceding randomization
• severe/uncontrollable adverse events with suspected relationship to everolimus (e.g. anemia, oral aphtosis, arthralgia) for the control of which the investigator has planned the withdrawal of everolimus
• severe infections requiring hospitalization in the two weeks preceding randomization
• poor compliance to prescribed treatments

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Perugia, Perugia, Italy

Novartis Investigative Site

Sassari, Sassari, Italy

Novartis Investigative Site

Ancona, , Italy

Novartis Investigative Site

Bologna, , Italy

Novartis Investigative Site

Brescia, , Italy

Novartis Investigative Site

Cagliari, , Italy

Novartis Investigative Site

Catania, , Italy

Novartis Investigative Site

Coppito, , Italy

Novartis Investigative Site

Florence, , Italy

Novartis Investigative Site

Genova, , Italy

Novartis Investigative Site

Milan, , Italy

Novartis Investigative Site

Modena, , Italy

Novartis Investigative Site

Napoli, , Italy

Novartis Investigative Site

Novara, , Italy

Novartis Investigative Site

Padua, , Italy

Novartis Investigative Site

Palermo, , Italy

Novartis Investigative Site

Parma, , Italy

Novarits Investigative Site

Pisa, , Italy

Novartis Investigative Site

Roma, , Italy

Novartis Investigative Site

Rome, , Italy

Novartis Investigative Site

Salerno, , Italy

Novartis Investigative Site

Siena, , Italy

Novartis Investigative Site

Torino, , Italy

Novartis Investigative Site

Treviso, , Italy

Novartis InvestigativeSite

Udine, , Italy

Novartis Investigative Site

Varese, , Italy

Novartis Investigative Site

Verona, , Italy

Novartis Investigative Site

Vicenza, , Italy

Countries

Italy

Other Identifiers

CRAD001AIT12

Identifier Type: -

Identifier Source: org_study_id