Differentiating Everolimus Versus Sirolimus in Combination With Calcineurin Inhibitors in Kidney Transplant Patients

NCT ID: NCT02062892

Last Updated: 2014-12-02

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2014-06-30

Brief Summary

The investigators hypothesize that switching kidney transplant patients on tacrolimus/sirolimus long-term maintenance immunosuppressive drug regimens to tacrolimus/everolimus, will not only be safe, but will lead to better kidney function than patients staying on tacrolimus/sirolimus due to the lower potential of everolimus to enhance calcineurin inhibitors toxicity and/or its ability to even reverse some of the negative effects of calcineurin inhibitors on vascular endothelial and kidney function. To test this hypothesis vascular endothelial biomarkers will be analyzed in blood plasma samples and kidney dysfunction biomarkers in urine samples via liquid chromatography tandem mass spectrometry to evaluate whether switching kidney transplant patients on tacrolimus/sirolimus to tacrolimus/everolimus will lead to better kidney and endothelial function after one year and two years.

Conditions

Kidney Transplantation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Blinding Strategy: NONE

Study Groups

Everolimus / Tacrolimus

Patients will be stable kidney transplant patients who are receiving an immunosuppressive drug regimen based on tacrolimus and sirolimus. 24 hours after the last sirolimus dose, the patients randomized to the tacrolimus/everolimus arm of the study will be switched from sirolimus to everolimus 1:1 (same sirolimus as everolimus dose). Everolimus doses will be adjusted so that trough blood concentrations are within 3-8 ng/mL. In detail: Tacrolimus (Prograf or FDA approved generic 0.5 mg, 1 mg or 5 mg capsules, twice a day) in combination with Everolimus (Zortress, 0.25, 0.5 and 0.75 tablets).

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

Patients will be stable kidney transplant patients who are receiving an immunosuppressive drug regimen based on tacrolimus and sirolimus. 24 hours after the last sirolimus dose, the patients randomized to the tacrolimus/everolimus arm of the study will be switched from sirolimus to everolimus 1:1 (same sirolimus as everolimus dose). Everolimus doses will be adjusted so that trough blood concentrations are within 3-8 ng/mL. In detail: Tacrolimus (Prograf or FDA approved generic 0.5 mg, 1 mg or 5 mg capsules, twice a day) in combination with Everolimus (Zortress, 0.25, 0.5 and 0.75 tablets).

Sirolimus / Tacrolimus

Patients will be stable kidney transplant patients who are receiving an immunosuppressive drug regimen based on tacrolimus and sirolimus. 24 hours after the last sirolimus dose, the patients randomized to the tacrolimus/sirolimus arm of the study will remain on tacrolimus/sirolimus. In detail: Tacrolimus (Prograf or FDA approved generic 0.5 mg, 1 mg or 5 mg capsules, once a day) in combination with Sirolimus (Rapamune, 0.5, 1, and 2mg tablets).

Group Type: ACTIVE_COMPARATOR

Sirolimus

Intervention Type: DRUG

Patients will be stable kidney transplant patients who are receiving an immunosuppressive drug regimen based on tacrolimus and sirolimus. 24 hours after the last sirolimus dose, the patients randomized to the tacrolimus/sirolimus arm of the study will remain on tacrolimus/sirolimus. In detail: Tacrolimus (Prograf or FDA approved generic 0.5 mg, 1 mg or 5 mg capsules, once a day) in combination with Sirolimus (Rapamune, 0.5, 1, and 2mg tablets).

Interventions

Everolimus

Patients will be stable kidney transplant patients who are receiving an immunosuppressive drug regimen based on tacrolimus and sirolimus. 24 hours after the last sirolimus dose, the patients randomized to the tacrolimus/everolimus arm of the study will be switched from sirolimus to everolimus 1:1 (same sirolimus as everolimus dose). Everolimus doses will be adjusted so that trough blood concentrations are within 3-8 ng/mL. In detail: Tacrolimus (Prograf or FDA approved generic 0.5 mg, 1 mg or 5 mg capsules, twice a day) in combination with Everolimus (Zortress, 0.25, 0.5 and 0.75 tablets).

Intervention Type: DRUG

Sirolimus

Patients will be stable kidney transplant patients who are receiving an immunosuppressive drug regimen based on tacrolimus and sirolimus. 24 hours after the last sirolimus dose, the patients randomized to the tacrolimus/sirolimus arm of the study will remain on tacrolimus/sirolimus. In detail: Tacrolimus (Prograf or FDA approved generic 0.5 mg, 1 mg or 5 mg capsules, once a day) in combination with Sirolimus (Rapamune, 0.5, 1, and 2mg tablets).

Intervention Type: DRUG

Other Intervention Names

Zortress

Eligibility Criteria

Inclusion Criteria

• Kidney transplant patients ≥ 3 months after transplantation. De novo patients on sirolimus and tacrolimus as well as patients switched to tacrolimus and sirolimus will be eligible as long as they have received this drug combination for at least 2 months.
• Immunosuppressive drug regimen based on tacrolimus and sirolimus
• 18-70 years of age
• calculated glomerular filtration rate≥ 30 mL/min/ 1.73m2 as calculated using the abbreviated Modification of Diet in Renal Disease formula
• Ability and willingness to provide written informed consent and adhere to study regimen.
• Patients who are able to take oral medication at time of randomization.

Exclusion Criteria

• Patients switched to tacrolimus and sirolimus due to clinically relevant nephrotoxicity of the previous immunosuppressive drug regimen,
• Patients with an abnormal liver profile such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or total bilirubin > 3 x upper limit of normal at time of randomization
• Patients with severe total hypercholesterolemia (> 350 mg/dL; > 9 mmol/L) or total hypertriglyceridemia (> 500 mg/dL; > 5.6 mmol/L). Patients on lipid lowering treatment with controlled hyperlipidemia are acceptable.
• Patients who tested positive for HIV, Hepatitis C or Hepatitis B surface antigen.
• An episode of acute rejection that required antibody therapy or more than one steroid sensitive episode of acute rejection prior to enrollment.
• Spot urine protein/creatinine ratio > 1g/24h at the time of randomization
• Multi-organ transplants
• Patients with platelet count < 50,000
• Patients with an absolute neutrophil count of < 1,000 or white blood cells of <2,000 at time of enrollment
• Patients with hemoglobin < 6g/dL
• Patients with clinically significant systemic infections requiring active use of IV antibiotics, anti-virales, or anti-fungals. Prophylactic use of anti-virales will be acceptable.
• Pregnancy or inability of practicing acceptable contraceptive measures.
• Patients who have any surgical or medical condition, such as severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus, which in the opinion of the investigator might significantly alter the absorption, distribution, metabolism and/or excretion of study medication.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Laurence Chan, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Clifford Miles, MD, MS

Role: PRINCIPAL_INVESTIGATOR

University of Nebraska

Other Identifiers

CRAD001AUS196T

Identifier Type: OTHER

Identifier Source: secondary_id

13-1583

Identifier Type: -

Identifier Source: org_study_id