Clinical trial NCT01935128: Evaluation of Calcineurin-inhibitor Reduction With Conversion at 2 Months to Everolimus/Reduced Tacrolimus in Renal Transplant Recipients Following Campath® Induction
Official title: A 24-month, Single Center, Pilot, Open Label, Controlled Trial to Evaluate the Efficacy and Safety of Calcineurin-inhibitor Reduction With Conversion at 2 Months to Reduced Dose Tacrolimus/Everolimus in Adult Renal Transplant Recipients Following Campath® Induction and Steroid Avoidance
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Renal Transplant
Keywords: Renal Transplant
Immunosuppression
Steroid Avoidance
Calcineurin Avoidance
Mammalian Target of Rapamycin (mTOR)
Kidney
Lead sponsor: University of Toledo
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2013-09-04
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate whether conversion to everolimus (Zortress®), allowing the elimination or reduction of calcineurin inhibitors, will reduce nephrotoxicity (measured by increased creatinine clearance) and lengthen overall graft (kidney transplant) survival (measured by 2-3 year graft survival).

Detailed description: The purpose of this study is to evaluate whether conversion to everolimus (Zortress®), allowing the elimination or reduction of calcineurin inhibitors, will reduce nephrotoxicity (measured by increased creatinine clearance) and lengthen overall graft (kidney transplant) survival (measured by 2-3 year graft survival). Among the worst of the long-term effects of chronic immunosuppression are the nephrotoxicity (toxic to kidney cells) of the calcineurin inhibitors and the myriad complications of steroids. This protocol evaluates the elimination or reduction of calcineurin inhibitors in a protocol that has already successfully eliminated the long-term use of steroids. A considerable need remains for safer therapeutic agents that inhibit T-cell activation (a white blood cell that attacks foreign cells as part of the immune response) via a calcineurin independent or reduced-dose mechanism of action.

Eligibility criteria: Inclusion Criteria:

* Male or female renal allograft recipients at least 18 years old.
* Patients who have given written informed consent to participate in the study. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness.
* Patient who has received a kidney transplant from a deceased or living unrelated-/related donor.
* Recipient of a kidney allograft with a cold ischemia time (CIT) \< 36 hours.
* Female patients must have a negative pregnancy test prior to study enrollment.
* Patients on calcineurin inhibitor(s) (CNI) (tacrolimus and myfortic®) without steroid maintenance following Campath® induction.
* Patients with an acceptable allograft function defined by a serum creatinine \< 2.5 mg/dL (250 μmol/L) and an actual estimated glomerular filtration rate (eGFR) (Modification of diet in renal disease equation 4, MDRD4) ≥ 30 mL/min/1.73m2 (without renal replacement therapy).
* No evidence of rejection since the time of transplantation.

Exclusion Criteria:

* Recipient of ABO incompatible allograft or a positive cross-match.
* Patient who is human immunodeficiency virus (HIV) positive.
* Patient who received an allograft from a Hepatitis B surface Antigen (HBsAg) or a Hepatitis C Virus (HCV) positive donor.
* HBsAg and/or a HCV positive patient with evidence of elevated liver function tests (LFTs) (Alanine transaminase/Aspartate transaminase \[ALT/AST\] levels ≥ 2.5 times upper limit of normal \[ULN\]). Viral serology results obtained within 6 months prior to randomization are acceptable.
* Patient with severe restrictive (total lung capacity \[TLC\] \< 50%) or obstructive pulmonary (forced expiratory volume in one second \[FEV1\] \< 50) disorders.
* Patient with severe allergy requiring acute (within 4 weeks of baseline) or chronic treatment that would prevent patient from potential exposure to everolimus, or with hypersensitivity to drugs similar to everolimus (e.g. macrolides).
* Patients with a known hypersensitivity/contraindication to any of the immunosuppressants or their classes, or to any of the excipients.
* Patient with severe hypercholesterolemia (\> 300 mg/dL) or hypertriglyceridemia (\> 400 mg/dL) that cannot be controlled despite lipid lowering therapy.
* Patient with white blood cell (WBC) count ≤ 1,000 /mm3 (and absolute neutrophil count \[ANC\] of \<500) or a platelet count ≤ 50,000 /mm3.
* History of malignancy of any organ system, treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. (Localized basal cell carcinoma of the skin at any time, or small (less than 4 cm) or low-grade renal cancers, bladder cancers, or treated prostate cancer with no evidence of disease after 2 years are allowable)
* Graft loss.
* Patient on renal replacement therapy.
* Patient who experienced biopsy proven rejection.
* Proteinuria \> 1 g/day (as calculated from the urinary protein-to-creatinine ratio).
* Patients with recurrence of Focal Segmental Glomerulosclerosis (FSGS).
* Patient who has a current severe systemic infection according to the investigator judgment requiring continued therapy that would interfere with the objectives of the study.
* Patients with ongoing wound healing problems, clinically significant infection requiring continued therapy or other severe surgical complication in the opinion of the investigator.
* Presence of intractable immunosuppressant complications or side effects.
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum human chorionic gonadotrophin laboratory test (\>5 mIU/mL)
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.

Primary outcomes:
measure: Renal Function
timeFrame: 2 years
measure: Graft Survival
timeFrame: 2 years
measure: Biopsy Proven Acute Rejection
timeFrame: 2 years
measure: Patient Survival
timeFrame: 2 years
Secondary outcomes:
measure: Impaired Glucose Tolerance
timeFrame: 2 years
measure: Proteinuria
timeFrame: 2 years
measure: Lipid Levels
timeFrame: 2 years
measure: Mouth Ulcers
timeFrame: 2 years
measure: Gastrointestinal Complaints
timeFrame: 2 years
measure: Leukopenia
timeFrame: 2 years
measure: Thrombocytopenia
timeFrame: 2 years
measure: Neurotoxicity
timeFrame: 2 years
measure: Pneumonitis
timeFrame: 2 years
measure: Cytomegalovirus
timeFrame: 2 years
measure: Infection Requiring Hospitalization
timeFrame: 2 years
measure: BK Infection
timeFrame: 2 years
measure: BK Nephropathy
timeFrame: 2 years
measure: Malignancies
timeFrame: 2 years
measure: Cardiovascular Complications
timeFrame: 2 years
measure: Development of Donor Specific Antibody
timeFrame: 2 years
Other outcomes:
Locations:
city: Toledo
country: United States
facility: University of Toledo, Health Science Campus
state: Ohio
Study officials:
affiliation: University of Toledo, HSC
name: Michael Rees, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: