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A Pilot Study Comparing the Safety and Efficacy of Everolimus With Other Medicines in Recipients of ECD/DCD Kidneys (Evered)

Primary Purpose

Delayed Graft Function

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Everolimus
Tacrolimus
Mycophenolate mofetil (MMF/MPA)
Sponsored by
Matthew Cooper
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Delayed Graft Function focused on measuring kidney failure

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female recipients 18-65 years of age undergoing primary or secondary kidney transplantation

Recipients of primary or secondary cadaveric, ECD/DCD kidney (defined as follows)

Donor whose heart has irreversibly stopped beating, previously referred to as non-heart-beating or asystolic donation

Brain-dead donor > 60 years old

Donor aged 50-59 years old with two of the following criteria:

History of hypertension

Terminal serum creatinine ≥ 1.5 mg/dL

Death resulting from cerebrovascular accident

Patients who have given written informed consent to participate in the study

Exclusion Criteria:

Cold ischemic time (CIT) > 30 hours

Patients who are ABO incompatible transplants, or T, or B cell crossmatch positive transplant

Patients with a known hypersensitivity to any of the study drugs or to drugs of similar chemical class

Non-controlled DCD

Donor age >70

Patients with BMI >32 at baseline before surgery

Pregnant or lactating females

Females of childbearing potential unwilling to use an effective means of contraception or are planning to become pregnant

Patients with platelet count <100,000/mm3 at the evaluation before randomization.

Patients with an absolute neutrophil count of < 1,500/mm³ at baseline before surgery or white blood cell count of < 4,500/mm³

Patients who are recipients of multiple solid organ transplants

Patients who have severe hypercholesterolemia (>350 mg/dL; >9 mmol/L) or hypertriglyceridemia (>500 mg/dL; >5.6 mmol/L). Patients with controlled hyperlipidemia are acceptable

Patients who have an abnormal liver profile such as ALT, AST, Alk Phos or total bilirubin >3 times the upper normal limit

Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4, such as terfenadine, astemizole, cisapride, erythromycin, azithromycin, itraconazole, rifampin or lovastatin

Patients who received an investigational drug or who have been treated with a non-protocol immunosuppressive drug or treatment within 30 days or 5 half-lives prior to randomization

Patients with a history of malignancy of any organ system, treated or untreated, within the past 2 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin

Patients who are HIV-positive or Hepatitis C (PCR+ only) or B surface antigen positive

Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C (PCR+ only) are excluded

Patients with a history of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus (Hgb A1c <7.0 %) at baseline

Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study medication, and/or the presence of severe diarrhea or active peptic ulcer

Patients who have cardiac failure (e.g. resting dyspnea, symptoms with less than ordinary activity, marked limitation of activity) at time of screening or any other severe cardiac disease as determined by the investigator

Patients with abnormal physical or laboratory findings of clinical significance within 3 months of randomization which would interfere with the objectives of the study

Patients with any history of coagulopathy or medical condition requiring long-term anticoagulation therapy after transplantation (Low dose aspirin treatment is allowed)

Patients with known history of focal segmental glomeruloscrelosis

Presence of psychiatric illness (i.e., schizophrenia, bipolar, major depression) that, in the opinion of the investigator, would interfere with study requirements

Sites / Locations

  • Georgetown University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

ERL & TAC

ERL & TAC --> MMF/MPA

Standard dose TAC + MMF/MPA

Arm Description

Concentration controlled everolimus(ERL) & Low dose tacrolimus(TAC) + corticosteroid withdraw

Concentration controlled everolimus & low dose tacrolimus --> mycophenolate mofetil (MMF) at Month 3 + corticosteroid

Standard dose of tacrolimus + mycophenolate mofetil + corticosteroid withdraw

Outcomes

Primary Outcome Measures

Evaluate Concentration-controlled Everolimus and Low Dose Tacrolimus Compared to MMF/MPA With Standard Dose Tacrolimus at 24 Months
The primary objective of this study is to evaluate concentration-controlled everolimus and low dose tacrolimus compared to MMF/MPA with standard dose tacrolimus at 24 months post-transplant with respect to the composite efficacy failure rates (treated biopsy proven acute rejection episodes (BPAR), graft loss, death, loss to follow-up) in de novo renal transplant recipients.

Secondary Outcome Measures

Compare Renal Function of the Everolimus Treatment Arms to the MMF/MPA Treatment Arm at 12 and 24 Months Post-transplantation
The key secondary objective is to compare renal function of the everolimus treatment arms to the MMF/MPA treatment arm at 12 and 24 months post-transplantation. Renal function will be measured by the calculated glomerular filtration rate (GFR), using the MDRD (Modification of Diet in Renal Disease) formula (20).

Full Information

First Posted
June 11, 2013
Last Updated
April 4, 2019
Sponsor
Matthew Cooper
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1. Study Identification

Unique Protocol Identification Number
NCT01878786
Brief Title
A Pilot Study Comparing the Safety and Efficacy of Everolimus With Other Medicines in Recipients of ECD/DCD Kidneys
Acronym
Evered
Official Title
A Pilot Study Comparing the Safety and Efficacy of Zortress (Everolimus) With Low Dose Tacrolimus to Early Conversion to Calcineulin Inhibitor-Free Regimen and Mycophenolic Acid With Standard Dose Tacrolimus in Recipients of ECD/DCD Kidneys
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Terminated
Why Stopped
Interim results suggested a concern for patient outcomes and safety
Study Start Date
June 2013 (undefined)
Primary Completion Date
November 2017 (Actual)
Study Completion Date
December 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Matthew Cooper

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this pilot study is to evaluate concentration-controlled everolimus with low dose tacrolimus compared to early conversion to CNI-free regimen and MMF/MPA with standard dose tacrolimus in de novo renal transplant recipients of ECD/DCD kidneys. Given tacrolimus and MMF/MPA is a widely prescribed immunosuppressive regimen in the United States, comparisons of tacrolimus and MMF/MPA regimens to investigational therapies and treatment regimens are needed. Also, considering the fact that ECD/DCD is a fast growing fraction of donors, evaluation of various regimens' effects on rather delicate ECD/DCD kidneys is necessary.
Detailed Description
The purpose of this pilot study is to evaluate concentration-controlled everolimus with low dose tacrolimus compared to early conversion to CNI-free regimen and MMF/MPA with standard dose tacrolimus in de novo renal transplant recipients of ECD/DCD kidneys. Given tacrolimus and MMF/MPA is a widely prescribed immunosuppressive regimen in the United States, comparisons of tacrolimus and MMF/MPA regimens to investigational therapies and treatment regimens are needed. Also, considering the fact that ECD/DCD is a fast growing fraction of donors, evaluation of various regimens' effects on rather delicate ECD/DCD kidneys is necessary. The primary objective of this study is to evaluate concentration-controlled everolimus and low dose tacrolimus compared to MMF/MPA with standard dose tacrolimus at 24 months post-transplant with respect to the composite efficacy failure rates (treated biopsy proven acute rejection episodes (BPAR), graft loss, death, loss to follow-up) in de novo renal transplant recipients. The key secondary objective is to compare renal function of the everolimus treatment arms to the MMF/MPA treatment arm at 12 and 24 months post-transplantation. Renal function will be measured by the calculated glomerular filtration rate (GFR), using the MDRD (Modification of Diet in Renal Disease) formula (20).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Delayed Graft Function
Keywords
kidney failure

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ERL & TAC
Arm Type
Experimental
Arm Description
Concentration controlled everolimus(ERL) & Low dose tacrolimus(TAC) + corticosteroid withdraw
Arm Title
ERL & TAC --> MMF/MPA
Arm Type
Experimental
Arm Description
Concentration controlled everolimus & low dose tacrolimus --> mycophenolate mofetil (MMF) at Month 3 + corticosteroid
Arm Title
Standard dose TAC + MMF/MPA
Arm Type
Experimental
Arm Description
Standard dose of tacrolimus + mycophenolate mofetil + corticosteroid withdraw
Intervention Type
Drug
Intervention Name(s)
Everolimus
Other Intervention Name(s)
Zortress
Intervention Description
One of the immunosuppressants currently being evaluated to replace CNIs in patients with CNI nephropathy is the mammalian Target of Rapamycin (mTOR) inhibitor, Sirolimus. Everolimus is a derivative of Sirolimus and belongs to this class of immunosuppressants, therefore, both drugs have similar side effect profile. The half-life of Everolimus is almost half of Sirolimus (Everolimus 30 hours vs Sirolimus 62 hours), which makes its dose adjustment easier although it would require more frequent dosing. In clinical trials, Everolimus has demonstrated its potential role as a safe alternative in minimizing and/or eliminating CNI such as Cyclosporin A and Tacrolimus .
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
Prograf
Intervention Description
One of the immunosuppressants currently being evaluated to replace CNIs in patients with CNI nephropathy is the mammalian Target of Rapamycin (mTOR) inhibitor, Sirolimus. Everolimus is a derivative of Sirolimus and belongs to this class of immunosuppressants, therefore, both drugs have similar side effect profile. The half-life of Everolimus is almost half of Sirolimus (Everolimus 30 hours vs Sirolimus 62 hours), which makes its dose adjustment easier although it would require more frequent dosing. In clinical trials, Everolimus has demonstrated its potential role as a safe alternative in minimizing and/or eliminating CNI such as Cyclosporin A and Tacrolimus.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF/MPA)
Other Intervention Name(s)
CellCept
Intervention Description
Control Drug
Primary Outcome Measure Information:
Title
Evaluate Concentration-controlled Everolimus and Low Dose Tacrolimus Compared to MMF/MPA With Standard Dose Tacrolimus at 24 Months
Description
The primary objective of this study is to evaluate concentration-controlled everolimus and low dose tacrolimus compared to MMF/MPA with standard dose tacrolimus at 24 months post-transplant with respect to the composite efficacy failure rates (treated biopsy proven acute rejection episodes (BPAR), graft loss, death, loss to follow-up) in de novo renal transplant recipients.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Compare Renal Function of the Everolimus Treatment Arms to the MMF/MPA Treatment Arm at 12 and 24 Months Post-transplantation
Description
The key secondary objective is to compare renal function of the everolimus treatment arms to the MMF/MPA treatment arm at 12 and 24 months post-transplantation. Renal function will be measured by the calculated glomerular filtration rate (GFR), using the MDRD (Modification of Diet in Renal Disease) formula (20).
Time Frame
24 months
Other Pre-specified Outcome Measures:
Title
Incidence of Cytomegalovirus (CMV) (Viremia or Viruria)
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female recipients 18-65 years of age undergoing primary or secondary kidney transplantation Recipients of primary or secondary cadaveric, ECD/DCD kidney (defined as follows) Donor whose heart has irreversibly stopped beating, previously referred to as non-heart-beating or asystolic donation Brain-dead donor > 60 years old Donor aged 50-59 years old with two of the following criteria: History of hypertension Terminal serum creatinine ≥ 1.5 mg/dL Death resulting from cerebrovascular accident Patients who have given written informed consent to participate in the study Exclusion Criteria: Cold ischemic time (CIT) > 30 hours Patients who are ABO incompatible transplants, or T, or B cell crossmatch positive transplant Patients with a known hypersensitivity to any of the study drugs or to drugs of similar chemical class Non-controlled DCD Donor age >70 Patients with BMI >32 at baseline before surgery Pregnant or lactating females Females of childbearing potential unwilling to use an effective means of contraception or are planning to become pregnant Patients with platelet count <100,000/mm3 at the evaluation before randomization. Patients with an absolute neutrophil count of < 1,500/mm³ at baseline before surgery or white blood cell count of < 4,500/mm³ Patients who are recipients of multiple solid organ transplants Patients who have severe hypercholesterolemia (>350 mg/dL; >9 mmol/L) or hypertriglyceridemia (>500 mg/dL; >5.6 mmol/L). Patients with controlled hyperlipidemia are acceptable Patients who have an abnormal liver profile such as ALT, AST, Alk Phos or total bilirubin >3 times the upper normal limit Patients who are treated with drugs that are strong inducers or inhibitors of cytochrome P450 3A4, such as terfenadine, astemizole, cisapride, erythromycin, azithromycin, itraconazole, rifampin or lovastatin Patients who received an investigational drug or who have been treated with a non-protocol immunosuppressive drug or treatment within 30 days or 5 half-lives prior to randomization Patients with a history of malignancy of any organ system, treated or untreated, within the past 2 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin Patients who are HIV-positive or Hepatitis C (PCR+ only) or B surface antigen positive Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C (PCR+ only) are excluded Patients with a history of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus (Hgb A1c <7.0 %) at baseline Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study medication, and/or the presence of severe diarrhea or active peptic ulcer Patients who have cardiac failure (e.g. resting dyspnea, symptoms with less than ordinary activity, marked limitation of activity) at time of screening or any other severe cardiac disease as determined by the investigator Patients with abnormal physical or laboratory findings of clinical significance within 3 months of randomization which would interfere with the objectives of the study Patients with any history of coagulopathy or medical condition requiring long-term anticoagulation therapy after transplantation (Low dose aspirin treatment is allowed) Patients with known history of focal segmental glomeruloscrelosis Presence of psychiatric illness (i.e., schizophrenia, bipolar, major depression) that, in the opinion of the investigator, would interfere with study requirements
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Matthew Cooper
Organizational Affiliation
Georgetown University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Georgetown University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States

12. IPD Sharing Statement

Learn more about this trial

A Pilot Study Comparing the Safety and Efficacy of Everolimus With Other Medicines in Recipients of ECD/DCD Kidneys

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