Extension Study to Evaluate the Long-term Efficacy and Safety of Everolimus in Liver Transplant Recipients

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

• Ages 20 to 75 years
• All sexes
• No healthy volunteers
• Adult, Older adult

Trial locations and contacts

57 sites in 16 countries.

About this study

Official title: Extension Study to the Multicenter, Open-label, Randomized, Controlled Study CRAD001H2304 to Evaluate the Long-term Efficacy and Safety of Concentration-controlled Everolimus in Liver Transplant Recipient

Conditions

Liver Transplant Recipient

Being tested

Tacrolimus (reduced tacrolimus), Everolimus (reduced tacrolimus), Tacrolimus (tacrolimus elimination), Everolimus (tacrolimus elimination), Tacrolimus (tacrolimus control)

Keywords

Liver transplantation, Everolimus, Calcineurin inhibitors, Tacrolimus, Renal function, Progression of HCV related allograft fibrosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

• Tacrolimus (reduced tacrolimus)Drug

  Also called FK-506,, fujimycin,, Prograf,, Advagraf,

  After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization, a level which was maintained for the duration of the study.

• Everolimus (reduced tacrolimus)Drug

  Also called RAD001,, Zortress,, Certican,, Afinitor

  Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL for the duration of the study.

• Tacrolimus (tacrolimus elimination)Drug

  Also called FK-506,, fujimycin,, Prograf,, Advagraf,

  After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization. Tacrolimus elimination was started beginning at Month 4. Tacrolimus was tapered after everolimus whole blood trough levels were within the target range of 6-10 ng/mL. Tacrolimus was completely eliminated by the end of Month 4.

• Everolimus (tacrolimus elimination)Drug

  Also called RAD001,, Zortress,, Certican,, Afinitor

  Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL until Month 4; beginning with Month 4, the dose was adjusted to maintain everolimus trough blood levels between 6-10 ng/mL.

• Tacrolimus (tacrolimus control)Drug

  Also called FK-506,, fujimycin,, Prograf,, Advagraf,

  Tacrolimus trough levels were targeted to be maintained at 8-12 ng/mL until Month 4. At Month 4, tacrolimus whole blood trough levels were decreased to a target trough level of 6-10 ng/mL for the remainder of the study.

• CorticosteroidsDrug

  For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids could be used for the duration of the study but could not be eliminated before Month 6. The corticosteroids were not specified in the protocol because they were adminsitered to the participants according to local practice as part of standard of care.

What is being measured

The primary outcome is the main question the study is designed to answer.

1. Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death

   The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.

   Measured: from months 24 to 36

2. Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death

   The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.

   Measured: from months 36 to 48

3. Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death

   The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.

   Measured: from months 24 to 36

4. Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death

   The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.

   Measured: from months 36 - 48

5. Change in Renal Function

   Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m^2) = 186.3*(C^-1.154)*(A^-0.203)*G*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1.

   Measured: from months 24 to 36

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1. First posted24 Jun 2010 (estimated)
2. Study start31 Mar 2010
3. Primary completion3 May 2013
4. Study completion3 May 2013

Resources

• Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
• Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
• Other trials for Liver Transplant RecipientStudies of the same condition, open and under way.
• More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
• What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.