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.

NCT01023815 | Completed Phase 3 Results

• 1 other identifier: CRAD001AIT12
• Study Type: interventional
• Target: 330
• Locations: 1 country
• Sites: 28

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

Keywords

Immunosuppression; renal transplantation; once-a-day regimen; steroid withdrawal; drug minimization; immunosuppression for prevention of acute rejections

Outcome Measures

Primary Outcomes (1)

• Treatment Failure Rate

  Occurrence or not of treatment failure in each patient. Treatment failure was defined as a composite endpoint of biopsy-proven acute rejection (a biopsy graded IA, IB, IIA, IIB or III according to Banff '97 grading with 2007 update), graft loss, death or lost to follow-up occurring after randomization (V5) and within M12 (V9).

  Between randomization (Month 3) and Month 12

Secondary Outcomes (5)

• Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12

  Month 3 to Month 12

• Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12

  Month 3 to Month 12

• Number of Participants With Graft and Patient Survival After Randomization

  Month 3 to Month 12

• Change in Estimated Creatine Clearance

  M3, M12

• Change in Serum Creatinine

  M3, M12

Study Arms (4)

Group A -Once-a-day regimen

EXPERIMENTAL

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.

Drug: everolimus; Drug: cyclosporine; Drug: Prednison (continuous steroids)

Group B - Steroid Withdrawal group

EXPERIMENTAL

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.

Drug: everolimus; Drug: cyclosporine; Drug: Prednison (continuous steroids)

Group C - Standard twice-a-day group

ACTIVE COMPARATOR

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.

Drug: everolimus; Drug: cyclosporine; Drug: Prednison (continuous steroids)

Not Randomized Population (NRP)

EXPERIMENTAL

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.

Drug: everolimus

Interventions

everolimus 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.

Also known as: Certican®)

Group A -Once-a-day regimen; Group B - Steroid Withdrawal group; Group C - Standard twice-a-day group; Not Randomized Population (NRP)

cyclosporine 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.

Also known as: CsA, Sandimmun® Neoral®

Group A -Once-a-day regimen; Group B - Steroid Withdrawal group; Group C - Standard twice-a-day group

Prednison (continuous steroids) DRUG

continuous steroids

Group A -Once-a-day regimen; Group B - Steroid Withdrawal group; Group C - Standard twice-a-day group

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis: lead

Study Sites (28)

Novartis Investigative Site

Perugia, Perugia, 06070, Italy

Location

Novartis Investigative Site

Sassari, Sassari, 07100, Italy

Location

Novartis Investigative Site

Ancona, 60100, Italy

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Novartis Investigative Site

Bologna, Italy

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Novartis Investigative Site

Brescia, Italy

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Novartis Investigative Site

Cagliari, Italy

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Novartis Investigative Site

Catania, Italy

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Novartis Investigative Site

Coppito, Italy

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Novartis Investigative Site

Florence, Italy

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Novartis Investigative Site

Genova, 16132, Italy

Location

Novartis Investigative Site

Milan, 20122, Italy

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Novartis Investigative Site

Modena, 41100, Italy

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Novartis Investigative Site

Napoli, Italy

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Novartis Investigative Site

Novara, 28100, Italy

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Novartis Investigative Site

Padua, Italy

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Novartis Investigative Site

Palermo, Italy

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Novartis Investigative Site

Parma, Italy

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Novarits Investigative Site

Pisa, Italy

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Novartis Investigative Site

Roma, Italy

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Novartis Investigative Site

Rome, Italy

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Novartis Investigative Site

Salerno, Italy

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Novartis Investigative Site

Siena, 53100, Italy

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Novartis Investigative Site

Torino, 10126, Italy

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Novartis Investigative Site

Treviso, Italy

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Novartis InvestigativeSite

Udine, Italy

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Novartis Investigative Site

Varese, Italy

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Novartis Investigative Site

Verona, Italy

Location

Novartis Investigative Site

Vicenza, Italy

Location

MeSH Terms

Interventions

Everolimus; Cyclosporine

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

trialandresults.registries@novartis.com

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

Study Record Dates

• First Submitted: December 1, 2009
• First Posted: December 2, 2009
• Study Start: April 1, 2009
• Primary Completion: July 1, 2012
• Study Completion: July 1, 2012
• Last Updated: July 19, 2016
• Results First Posted: November 14, 2013

Record last verified: 2016-06

Locations

IT (28)