Preservation of Renal Function in Liver Transplant Recipients With Certican Therapy

Presentation of Renal Function in Liver Transplant Recipients With Certican Therapy: PROTECT Study A Twelve-month, Multicenter, Randomized, Open-label Study of Safety, Tolerability and Efficacy of Certican-based Regimen Versus Calcineurin Inhibitor-based Regimen in de Novo Liver Transplant Recipients

The study is designed to show that everolimus initiation together with reduction and thereafter discontinuation of calcineurin inhibitor (CNI) will improve significantly renal function in de novo liver transplant recipients as compared to continuation of CNI-based treatment.

Study Overview

• Status: Completed
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: basiliximab; Drug: CNI; Drug: everolimus

• Study Type: Interventional
• Enrollment (Actual): 276
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, A-6020
    • Novartis Investigative Site
  • Wien, Austria, A-1090
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Jena, Germany, 07740
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • Regensburg, Germany, 93053
    • Novartis Investigative Site
  • Tübingen, Germany, 72076
    • Novartis Investigative Site
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3015 CE
    • Novartis Investigative Site
• Switzerland
  • Genève, Switzerland, 1211
    • Novartis Investigative Site
  • Zurich, Switzerland, 8091
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females 18 - 70 years old
• Liver transplant recipient (living or deceased donor)
• Patients in whom an allograft biopsy will not be contraindicated

Exclusion Criteria:

• Recipients of multiple solid organ transplants or patients that have already received a transplant in the past
• HCV positive patients who need an active anti-viral treatment (HCV- positive patients without active antiviral treatment are allowed)
• HIV positive patients
• Patients who are breast feeding
• Patients with a current severe systemic infection
• Presence of any hypersensitivity to drugs similar to Certican® (e.g. macrolides)
• Preexisting (i.e. not related to CNI-damage) renal dysfunction that, according to the judgment of the investigator, will not significantly improve after transplantation (i.e., for example, patients that are expected to have a cGFR below 50ml/min at 4 weeks post transplantation)
• Patients that have received Simulect prior to this study.
• Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus; Basiliximab plus everolimus-based immunosuppressive regimen following the reduction and cessation of initial CNI regimen plus optional steroids according to local best practice	Drug: basiliximab; All patients who met the eligibility criteria were treated with 2 doses of basiliximab on Day 0 (transplantation) and Day 4.; Other Names: simulect; Drug: CNI; Patients who met the screening eligibility received CNI-based immunosuppressive therapy for 1 month. Then at week 4 (or week 8 at maximum), patients randomized to the CNI arm continued on CNI-based immunosuppressive therapy.
Active Comparator: Calcineurin Inhibitor (CNI); Basiliximab plus CNI-based immunosuppressive regimen according to local best practice plus optional steroids according to local best practice	Drug: basiliximab; All patients who met the eligibility criteria were treated with 2 doses of basiliximab on Day 0 (transplantation) and Day 4.; Other Names: simulect; Drug: CNI; Patients who met the screening eligibility received CNI-based immunosuppressive therapy for 1 month. Then at week 4 (or week 8 at maximum), patients randomized to the CNI arm continued on CNI-based immunosuppressive therapy.; Drug: everolimus; Start dose of everolimus was 1.5 mg in the morning followed by 1.5 mg in the evening. After one week, the dose was adjusted to achieve trough levels between 5-12 ng/mL. Once trough levels were above 5ng/mL, the CNI dose was reduced to 70%. At week 8 post-baseline (latest at week 16 post baseline), CNI was completely discontinued. For patients receiving Ciclosporin A (CiA) as CNI, the everolimus dosage was adjusted to achieve a trough level of 8-12 ng/mL, prior to discontinuation of CiA. After discontinuation of CNI, everolimus was maintained at a trough level of 5-12 ng/mL.; Other Names: certican

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Calculated Glomerular Filtration Rate (cGFR)	This outcome measure evaluated renal function by assessing the calculated GFR based on the Cockcroft-Gault formula.	Month 11

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Efficacy Failure	Efficacy failure was defined as the composite endpoint of biopsy-proven acute rejection (BPAR), graft loss, death, lost to follow-up (from any reason), whichever occurred first. Incidence of efficacy failure was estimated using crude rate estimation (relative frequency).	Month 11
Incidence of the Need for a Change in the Immunosuppressive Regimen	The incidence of any changes in the immunosuppressive regimen other than allowed in the study protocol (for example, introduction of Mycophenolic acid (MPA) or sirolimus) was estimated using crude rate estimation (relative frequency).	Month 11
Incidence of Renal Deterioration	Renal deterioration was defined as a decrease by ≥25% in the cGFR compared to baseline and confirmed by one consecutive measurement. The analysis of this outcome measure was omitted because of missing relevance.	Baseline, Month 11
Renal Function (cGFR)	This outcome measure evaluated renal function by assessing the calculated GFR based on the Cockcroft-Gault formula.	Month 5
Incidence of Treated BPAR	The incidence of treated BPAR was estimated using crude rate estimation (relative frequency).	Month 11
Patient and Graft Survival	Patient survival was defined as the time from date of randomization to date of death from any cause. If a patient was not known to have died, patient survival was censored as the date of last contact. Graft survival was defined as the time from the date of randomization to the date of graft loss. If a patient was not known to suffer from a graft loss or died without graft loss, time to graft loss was censored with date of last contact or date of death, respectively. Patient and graft survival were analyzed using the Kaplan Meier method.	Month 11
Hepatitis C Virus (HCV) Replication in HCV-positive Patients	HCV ribonucleic acid (RNA) was measured by real time reverse transcriptase polymerase chain reaction (PCR; copies per mL).	Baseline, Month 5
Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death	Patients with all (serious and non-serious) adverse events, serious adverse events and death were reported.	From randomization to Month 11
Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death	Patients with all (serious and non-serious) adverse events, serious adverse events and death were reported.	Month 12 to Month 59 post-baseline

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: September 15, 2006
• First Submitted That Met QC Criteria: September 18, 2006
• First Posted (Estimate): September 19, 2006

Study Record Updates

• Last Update Posted (Estimate): February 6, 2015
• Last Update Submitted That Met QC Criteria: January 19, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: Liver transplantation, everolimus, CNI
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus; Basiliximab
• Other Study ID Numbers: CRAD001HDE10; 2005-002920-32