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

Differentiating Sirolimus and Everolimus in Combination With Calcineurin Inhibitors in Long-term Maintenance of Kidney Transplant Patients - The Effects on Vascular Endothelial and Kidney Function. The DESIRE Study.

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.

Study Overview

• Status: Withdrawn
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Everolimus; Drug: Sirolimus

• Study Type: Interventional
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: 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).; Other Names: Zortress
Active Comparator: 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).	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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Creatinine Outcome Measure (1)	Kidney function outcome markers will be assessed one year after kidney transplant	1 year
Calculated Glomerular Filtration Rate (1)	Kidney function outcome markers will be assessed one year after kidney transplant	1 year
Calculated Glomerular Filtration Rate (2)	Kidney function outcome markers will be assessed two years after kidney transplant	2 years
Kidney Injury Molecule-1 (1)	Kidney function outcome markers will be assessed one year after kidney transplant	1 year
Kidney Injury Molecule-1 (2)	Kidney function outcome markers will be assessed two years after kidney transplant	2 years
S-Adenosylhomocysteine Hydrolase (1)	Kidney function outcome markers will be assessed one year after kidney transplant	1 year
S-Adenosylhomocysteine Hydrolase (2)	Kidney function outcome markers will be assessed two years after kidney transplant	2 years
S-Adenosylmethionine (1)	Kidney function outcome markers will be assessed one year after kidney transplant	1 year
S-Adenosylmethionine (2)	Kidney function outcome markers will be assessed two years after kidney transplant	2 years
Creatinine Outcome Measure (2)	Kidney function outcome markers will be assessed two years after kidney transplant	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
12-Hydroxyeicosatetraenoic acid (1)	Vascular endothelial dysfunction outcome markers will be assessed one year after kidney transplant	1 year
12-Hydroxyeicosatetraenoic acid (2)	Vascular endothelial dysfunction outcome markers will be assessed two years after kidney transplant	2 years
20-Hydroxyeicosatetraenoic acid (1)	Vascular endothelial dysfunction outcome markers will be assessed one year after kidney transplant	1 year
20-Hydroxyeicosatetraenoic acid (2)	Vascular endothelial dysfunction outcome markers will be assessed two years after kidney transplant	2 years
18- Hydroxyeicosapentaenoic acid (1)	Vascular endothelial dysfunction outcome markers will be assessed one year after kidney transplant	1 year
18- Hydroxy- eicosapentaenoic acid (2)	Vascular endothelial dysfunction outcome markers will be assessed two years after kidney transplant	2 years
Ornithine (1)	Vascular endothelial dysfunction outcome markers will be assessed one year after kidney transplant	1 year
Ornithine (2)	Vascular endothelial dysfunction outcome markers will be assessed two years after kidney transplant	2 years
Arginine (1)	Vascular endothelial dysfunction outcome markers will be assessed one year after kidney transplant	1 year
Arginine (2)	Vascular endothelial dysfunction outcome markers will be assessed one year after kidney transplant	2 years

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Laurence Chan, MD, PhD, University of Colorado, Denver; Principal Investigator: Clifford Miles, MD, MS, University of Nebraska

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: February 11, 2014
• First Submitted That Met QC Criteria: February 12, 2014
• First Posted (Estimate): February 14, 2014

Study Record Updates

• Last Update Posted (Estimate): December 2, 2014
• Last Update Submitted That Met QC Criteria: December 1, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: biomarkers; Transplantation; kidney; everolimus; tacrolimus; sirolimus; vascular endothelial function
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Everolimus; Sirolimus
• Other Study ID Numbers: 13-1583; CRAD001AUS196T (Other Identifier)