Clinical trial NCT02062892: Differentiating Everolimus Versus Sirolimus in Combination With Calcineurin Inhibitors in Kidney Transplant Patients
Official title: 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.
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: Kidney Transplantation
Keywords: everolimus
sirolimus
tacrolimus
vascular endothelial function
kidney
Transplantation
biomarkers
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2014-02-14
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER

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.


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.

Primary outcomes:
measure: Creatinine Outcome Measure (1)
timeFrame: 1 year
measure: Calculated Glomerular Filtration Rate (1)
timeFrame: 1 year
measure: Calculated Glomerular Filtration Rate (2)
timeFrame: 2 years
measure: Kidney Injury Molecule-1 (1)
timeFrame: 1 year
measure: Kidney Injury Molecule-1 (2)
timeFrame: 2 years
measure: S-Adenosylhomocysteine Hydrolase (1)
timeFrame: 1 year
measure: S-Adenosylhomocysteine Hydrolase (2)
timeFrame: 2 years
measure: S-Adenosylmethionine (1)
timeFrame: 1 year
measure: S-Adenosylmethionine (2)
timeFrame: 2 years
measure: Creatinine Outcome Measure (2)
timeFrame: 2 years
Secondary outcomes:
measure: 12-Hydroxyeicosatetraenoic acid (1)
timeFrame: 1 year
measure: 12-Hydroxyeicosatetraenoic acid (2)
timeFrame: 2 years
measure: 20-Hydroxyeicosatetraenoic acid (1)
timeFrame: 1 year
measure: 20-Hydroxyeicosatetraenoic acid (2)
timeFrame: 2 years
measure: 18- Hydroxyeicosapentaenoic acid (1)
timeFrame: 1 year
measure: 18- Hydroxy- eicosapentaenoic acid (2)
timeFrame: 2 years
measure: Ornithine (1)
timeFrame: 1 year
measure: Ornithine (2)
timeFrame: 2 years
measure: Arginine (1)
timeFrame: 1 year
measure: Arginine (2)
timeFrame: 2 years
Other outcomes:
Locations:
Study officials:
affiliation: University of Colorado, Denver
name: Laurence Chan, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Nebraska
name: Clifford Miles, MD, MS
role: PRINCIPAL_INVESTIGATOR
References: