Evaluation of Calcineurin-inhibitor Reduction With Conversion at 2 Months to Everolimus/Reduced Tacrolimus in Renal Transplant Recipients Following Campath® Induction

NCT01935128 | Completed Phase 4 Results

• 1 other identifier: Everolimus
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

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).

Conditions

Renal Transplant

Keywords

Renal Transplant; Immunosuppression; Steroid Avoidance; Calcineurin Avoidance; Mammalian Target of Rapamycin (mTOR); Kidney

Outcome Measures

Primary Outcomes (4)

• Renal Function

  Renal function in patients will be assessed using glomerular filtration rate (GFR) as measured by the Modified Diet Renal Disease (MDRD) estimation. Glomerular filtration is the process by which the kidneys filter the blood, removing excess wastes and fluids. Glomerular filtration rate (GFR) is a calculation that determines how well the blood is filtered by the kidneys, which is one way to measure remaining kidney function. GFR is also used to find the stage of chronic kidney disease. Glomerular filtration rate is usually calculated using a mathematical formula that compares a person's size, age, sex, and race to serum creatinine levels. The higher the GFR number, the better the kidney function; the lower the GFR number, the worse the kidney function. A GFR of 60 or higher is in the normal range. A GFR below 60 may mean kidney disease. A GFR of 15 or lower may mean kidney failure.

  2 years

• Graft Survival

  Graft survival is defined as the percentage of kidney transplants still functioning at 2 years post baseline visit . One patient died of natural causes at 12 months with a functioning graft.

  2 years

• Biopsy Proven Acute Rejection

  The percentage of patients with a treated biopsy-proven acute rejection (a co-primary endpoint) within the 2 year study time period

  2 years

• Patient Survival

  Patient survival is defined as the percentage of patients still surviving at 2 years post baseline visit

  2 years

Secondary Outcomes (16)

• Impaired Glucose Tolerance

  2 years

• Proteinuria

  2 years

• Lipid Levels

  2 years

• Mouth Ulcers

  2 years

• Gastrointestinal Complaints

  2 years

Study Arms (1)

Arm 1 Everolimus/Reduced dose tacrolimus

EXPERIMENTAL

In this arm, the myfortic® will be weaned off quickly and everolimus (Zortress®) initiated to achieve a target level of 3-8 ng/ml with a mean of 6 ng/ml. Once achieving a therapeutic dose of everolimus (Zortress®) the tacrolimus (Prograf® or Hecoria®) dose will be reduced a target level of 3-5 ng/ml.

Drug: Arm 1 Everolimus/Reduced dose tacrolimus

Interventions

Arm 1 Everolimus/Reduced dose tacrolimus DRUG

Immunosuppression drug intervention

Also known as: Zortress®, Prograf® or Hecoria®

Arm 1 Everolimus/Reduced dose tacrolimus

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• University of Toledo Health Science Campus: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

University of Toledo, Health Science Campus

Toledo, Ohio, 43614, United States

Location

MeSH Terms

Conditions

Hereditary Sensory and Autonomic Neuropathies

Interventions

Everolimus; Tacrolimus

Condition Hierarchy (Ancestors)

Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

The study is limited by early discontinuation of the 2nd arm in this parallel group study due to safety concerns. All 5 patients with tacrolimus elimination developed donor specific antibodies against DQ-beta HLA antigens and were excluded from study analysis. Protocol section notes enrollment of 55 patients. Results for only 50 patients Due to small sample size, study is not powered to achieve statistical significance. Statistical significance also impaired without the 2nd arm of the study.

Results Point of Contact

• Title: Michael A. Rees, MD, PhD
• Organization: University of Toledo Medical Center

michael.rees2@utoledo.edu

419 383-3961

Study Officials

• Michael Rees, MD, PhD

  University of Toledo, HSC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 21, 2013
• First Posted: September 4, 2013
• Study Start: July 3, 2013
• Primary Completion: July 1, 2020
• Study Completion: July 1, 2020
• Last Updated: May 26, 2022
• Results First Posted: May 26, 2022

Record last verified: 2022-05

Locations

US (1)