RESCUE Study - Everolimus in Liver Transplantation Recipients With Renal Insufficiency

NCT00267189 | Completed Phase 3 Results DMC

• 1 other identifier: CRAD001H2401
• Study Type: interventional
• Target: 145
• Locations: 2 countries
• Sites: 2

Brief Summary

The purpose of the study is to assess the effect of everolimus initiation together with reduction or discontinuation of calcineurin inhibitor (CNI) on renal function in maintenance liver transplant recipients with CNI-related renal impairment, while maintaining efficacy.

Conditions

Liver Transplantation

Keywords

Liver transplantation, everolimus, calcineurin inhibitor, renal function

Outcome Measures

Primary Outcomes (1)

• Mean Change From Baseline in Cockcroft-Gault Calculated Creatinine Clearance (CrCl)

  The primary variable was renal function assessed by calculated creatinine clearance using the Cockcroft-Gault formula, and was assessed at all visits. CrCl\[mL/min\] = (140 - A) \* W / (72 \* C) \* R. Where A is age at sample date \[years\], W is body weight at specific visit \[kg\], C is the serum concentration of creatinine \[mg/dL\], R = 1 if the patient is male and = 0.85 if female.

  From baseline to 6 months

Secondary Outcomes (2)

• Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death)

  6 months

• Number of Patients With Discontinuation of Study Medication

  6 months

Study Arms (2)

Reduced CNI dose + everolimus ± steroids

ACTIVE COMPARATOR

Reduced CNI dose + everolimus (1.5 mg twice daily (b.i.d)) ± steroids

Drug: Everolimus; Drug: Calcineurin inhibitors (CNI); Drug: Steroids

CNI continuation ± MPA/AZA ± Steroids

EXPERIMENTAL

Standard CNI dose ± MPA/AZA ± steroids

Drug: Calcineurin inhibitors (CNI); Drug: Mycophenolate acid (MPA)/ Azathioprine (AZA); Drug: Steroids

Interventions

Everolimus DRUG

1.5 mg bid adjusted in order to achieve a trough level between 3 and 8 ng/mL while in combination with CNI and between 6 and 12 ng/mL after CNI discontinuation

Also known as: Certican, RAD001, Neoral®/Prograf®

Reduced CNI dose + everolimus ± steroids

Calcineurin inhibitors (CNI) DRUG

Also known as: Neoral/Prograf

CNI continuation ± MPA/AZA ± Steroids; Reduced CNI dose + everolimus ± steroids

Mycophenolate acid (MPA)/ Azathioprine (AZA) DRUG

Also known as: Myfortic/Cellecept

CNI continuation ± MPA/AZA ± Steroids

Steroids DRUG

CNI continuation ± MPA/AZA ± Steroids; Reduced CNI dose + everolimus ± steroids

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female 18 - 70 years old
• Patient who has undergone a primary liver transplantation 12 to 60 months ago from a cadaveric or a living donor
• Patient with a calculated GFR ≤ 60 and ≥ 20mL/min
• Patient receiving tacrolimus with C0-h level ≥ 3 and ≤ 8 ng/mL or Neoral® with C0-h level ≥ 50 and ≤ 150 ng/mL or with C2-h level ≥ 250 ng/mL and ≤ 650 ng/mL with or without any of the following (MPA or AZA or steroids)
• Patient willing and capable of giving written informed consent for study participation and able to participate in the study for 6 months
• Patient in whom an allograft biopsy will not be contraindicated
• Female capable of becoming pregnant must have a negative pregnancy test prior to randomization and are required to practice a medically approved method of birth control for the duration of the study

You may not qualify if:

• Recipient of multiple solid organ transplants
• Patient on dialysis
• Patient with an identifiable cause of renal dysfunction other than CNI toxicity
• Patient with proteinuria ≥ 1.0 g/24h
• Patient with any acute rejection within 6 months prior to randomization
• Patient with platelet count of ≤ 50,000/mm³ or white blood cell count of ≤ 2,000/mm³ or hemoglobin value ≤ 8 g/dL
• Undergone a liver transplantation for a hepatocellular carcinoma with sign of recurrence;
• Severe graft dysfunction;
• HCV positive patient who needs an active anti-viral treatment
• HIV positive patient
• Patient who is breast feeding
• Patient with a current severe systemic infection
• Patient who has received an unlicensed drug or therapy within one month prior to study entry
• Presence of any hypersensitivity to drugs similar to everolimus (e.g. macrolides)
• Use of any other immunosuppressive drugs than tacrolimus/cyclosporine microemulsion, steroids, azathioprine and mycophenolic acid

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (2)

Novartis Investigational Site

Germany, Germany

Location

Novartis Investigative Site

Basel, Switzerland

Location

Related Publications (2)

• De Simone P, Metselaar HJ, Fischer L, Dumortier J, Boudjema K, Hardwigsen J, Rostaing L, De Carlis L, Saliba F, Nevens F. Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: a prospective, randomized, multicenter trial. Liver Transpl. 2009 Oct;15(10):1262-9. doi: 10.1002/lt.21827.

  PMID: 19790150 RESULT

• Schrader J, Sterneck M, Klose H, Lohse AW, Nashan B, Fischer L. Everolimus-induced pneumonitis: report of the first case in a liver transplant recipient and review of treatment options. Transpl Int. 2010 Jan;23(1):110-3. doi: 10.1111/j.1432-2277.2009.00900.x. Epub 2009 May 29. No abstract available.

  PMID: 19497063 DERIVED

MeSH Terms

Interventions

Everolimus; Calcineurin Inhibitors; Cyclosporine; Tacrolimus; Azathioprine; Mycophenolic Acid; Steroids

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Thionucleosides; Sulfur Compounds; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Fused-Ring Compounds

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 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY

Study Record Dates

• First Submitted: December 19, 2005
• First Posted: December 20, 2005
• Study Start: November 1, 2005
• Primary Completion: November 1, 2007
• Study Completion: November 1, 2007
• Last Updated: April 13, 2011
• Results First Posted: April 7, 2011

Record last verified: 2011-04

Locations

CH (1); DE (1)