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Early Conversion From CNI to Belatacept in Renal Transplant Recipients With Delayed and Slow Graft Function

Primary Purpose

Delayed Graft Function, Kidney Transplant

Status
Unknown status
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Belatacept
Calcineurin Inhibitor
Sponsored by
Nair, Vinay, D.O.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Delayed Graft Function focused on measuring Delayed Graft Function, Renal Transplantation, Kidney Transplant

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Before any study procedures are performed, subjects will have the details of the study described to them, and they will be given a written informed consent document to read. Then, if subjects consent to participate in the study, they will indicate that consent by signing and dating the informed consent document in the presence of study personnel.
  • All patients (> 18 years) who have received a deceased donor transplant and are at risk for SGF/DGF will be studied
  • All gender and ethnicities will be considered in this study
  • At risk for SGF/DGF is defined as:

    • ECD (Extended Criteria Donor) donor kidney recipients
    • ECD is defined as a donor over the age of 60 or age 50 to 60 with 2 of the following risk factors:
  • Terminal creatinine > 1.5 mg/dL
  • History of Hypertension
  • Death due to cerebrovascular accident

    • Donations after cardiac death (DCD) kidney recipients
    • Donor organs with an actual cold ischemia time (CIT) > 19 hours
    • Recipients of donor organs with a terminal creatinine > 1.5 mg/dL
  • Only patients who receive Thymoglobulin induction and CNI maintenance at time of randomization will be considered for the study
  • Men and women, 18 to 70 years of age
  • Reproductive status: Definition of Women of Child-Bearing Potential (WOCBP). WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal.

Post-menopause is defined as:

  • Women who have had amenorrhea for >= 12 consecutive months (without another cause) and who have a documented serum follicle-stimulating hormone (FSH)level > 35 mIU/mL
  • Women who have irregular menstrual periods and a documented serum FSH level > 35 mIU/mL
  • Women who are taking hormone replacement therapy

The following are WOCBP:

  • Women using the following methods to prevent pregnancy: oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as intrauterine devices or barrier methods (diaphragm, condoms, spermicides).
  • Women who are practicing abstinence
  • Women who have a partner who is sterile (due to vasectomy)
  • WOCBP must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized
  • WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours before the first dose of study drug.
  • Women must not be breast-feeding
  • Sexually active fertile men must use effective birth control if their partners are WOCBP

Exclusion Criteria:

  • Seronegative or unknown EBV (Epstein Barr Virus) serostatus (due to the risk of posttransplant lymphoproliferative disorder, PTLD) predominantly involving the central nervous system
  • Patients with tuberculosis who have not been treated for latent infection
  • Patients at high risk for polyoma virus-associated nephropathy, which is mostly due to BK virus infection
  • Rejection episode before randomization
  • Anatomic cause of SGF/DGF such as urinary leak, obstruction or thrombosis
  • Patients with a prior or concurrent non-renal solid organ transplant
  • Patients with living donor kidneys
  • Patients with pediatric kidneys (age of less than 5 years)
  • Dual kidney transplants (from the same donor)
  • Immunologically high risk patients with a positive crossmatch pre- transplantation or donor specific antibody (DSA) > 5000 MFI
  • ABO Incompatible transplantation
  • Patients with HIV
  • Subjects with any active infection or other contraindication that would normally exclude transplantation
  • Patients with a history of malignancy in the last 5 years except non- melanoma skin cancer
  • Baseline white blood cell count less than 2,000
  • Baseline hemoglobin less than 8 g/dL
  • Patients with prior allergic reactions to belatacept
  • Patients with prior allergic reactions to thymoglobulin
  • Sex and Reproductive status - see WOCBP information in inclusion above
  • Subjects currently receiving immunosuppressive agent(s) for other indications such as an autoimmune disease or subjects with comorbidities that treatment with such agents are likely during the trial.
  • Subjects who have used any investigational drug within 30 days prior to the Day 1 visit
  • Subjects previously treated with belatacept
  • Prisoners or subjects who are involuntarily incarcerated
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.

Sites / Locations

  • Mount Sinai School of Medicine Recanati/Miller Transplantation InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Belatacept

Calcineurin Inhibitor

Arm Description

Subjects will be converted from standard of care CNI therapy to Belatacept 10 mg/kg IV on post renal transplant Day 7 (+/- 3 days). As suggested in the package insert for de novo dosing, further dosing of belatacept will be given as 10 mg/kg IV at weeks 2, 4, 8 and 12 then 5 mg/kg at week 16 and then every 4 weeks (+/- 5 days) through week 52. CNI will be stopped during the first belatacept infusion.

Patients randomized to this arm will remain on the current CNI as prescribed by post-transplant standard of care therapy.

Outcomes

Primary Outcome Measures

cGFR
Serum creatinine will be checked at each study visit from which GFR will be calculated. 12 month 4 variable MDRD calculated GFR will be compared between the belatacept conversion group and the calcineurin inhibitor group.

Secondary Outcome Measures

Renal Histology
Chronic Allograft Damage Index (CADI) and Interstitial Fibrosis/Tubular Atrophy (IFTA) renal pathology scores will be assessed by a local pathologist. CADI and IF/TA will be recorded at baseline (reperfusion biopsy) and at the 1 year protocol biopsy. The average progression of CADI and IF/TA will be compared in both groups and the average absolute CADI and IF/TA scores will be compared in both groups at 1 year post transplant.
Biomarker profile
The results of urine biomarkers (clusterin) will be correlated with the development of the primary and secondary endpoints in both groups. In this manner the investigators will be able to understand which genes/proteins are primarily altered by injury and assess how belatacept affects this process.
Duration of Delayed (or slow) Graft Function
The average duration of DGF/SGF will be compared in both belatacept and CNI groups
Incidence of Acute Rejection
Acute rejection by month 12 will be assessed by a local pathologist using the Banff 97 working classification of kidney transplant pathology. All biopsies will be interpreted locally for purposes of the study.
New Onset Diabetes
Subjects will be evaluated for post-transplant diabetes at visits after week 4.
Blood Pressure Control
Subjects are to be evaluated at each clinic visit to assess the need for adjustment of antihypertensive medication in order to achieve a BP of < 130/80 mmHg. Average systolic and diastolic blood pressure in both groups at Month 12, number of antihypertensive medications and change in intensity of hypertension treatment will be observed.
Dyslipidemia
Cholesterol levels in both groups, number of patients on dyslipidemic therapy at month 12 and change in intensity of dyslipidemia therapy will be observed
Graft Survival
Graft survival will be observed in both groups and compared at 12 months post-transplant
Patient survival
Patient survival will be observed in both groups and compared at 12 months post-transplant

Full Information

First Posted
April 16, 2013
Last Updated
January 27, 2017
Sponsor
Nair, Vinay, D.O.
Collaborators
Icahn School of Medicine at Mount Sinai, Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT01837043
Brief Title
Early Conversion From CNI to Belatacept in Renal Transplant Recipients With Delayed and Slow Graft Function
Official Title
A Randomized Trial of Early Conversion From Calcineurin Inhibitors (CNI) to Belatacept in Renal Transplant Recipients With Delayed and Slow Graft Function
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Unknown status
Study Start Date
June 2013 (undefined)
Primary Completion Date
June 2017 (Anticipated)
Study Completion Date
June 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nair, Vinay, D.O.
Collaborators
Icahn School of Medicine at Mount Sinai, Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety and efficacy of conversion from a calcineurin inhibitor (tacrolimus or cyclosporine) immunosuppression therapy to Nulojix® (belatacept) immunosuppression therapy in patients with delayed (DGF) or slow graft function (SGF) following kidney transplantation. Patients at risk for SGF or DGF will be consented at the time of kidney transplantation. On post-op Day 5 the patient will be assessed, if they have developed SGF or DGF they will be randomized to convert to Belatacept or continue on their CNI regimen. Up to 20 subjects who do not develop DGF will be followed as control subjects. Seventy randomized subjects will be followed for a total of 14 months with a renal biopsy at Month 12 post transplant. Research Hypotheses: Primary Hypotheses: Kidneys with slow or delayed graft function are more susceptible to acute and long-term CNI toxicity Kidneys converted from calcineurin inhibitor based therapy to belatacept will achieve a more rapid recovery from post-ischemic acute tubular necrosis (ATN) and will have improved 1 year calculated GFR. Key Secondary Hypotheses: Renal Histology: Belatacept converted patients will have a lower chronic allograft damage index (CADI) score and lower interstitial fibrosis and tubular atrophy (IF/TA) score as calculated by Banff criteria at 1 year post- transplant Biomarker Analysis: Biomarker analysis (clusterin) measured in serial urine collections can 1) directly assess CNI induced kidney injury and 2) improve the prediction of patients that benefit in early belatacept conversion.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Delayed Graft Function, Kidney Transplant
Keywords
Delayed Graft Function, Renal Transplantation, Kidney Transplant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Belatacept
Arm Type
Experimental
Arm Description
Subjects will be converted from standard of care CNI therapy to Belatacept 10 mg/kg IV on post renal transplant Day 7 (+/- 3 days). As suggested in the package insert for de novo dosing, further dosing of belatacept will be given as 10 mg/kg IV at weeks 2, 4, 8 and 12 then 5 mg/kg at week 16 and then every 4 weeks (+/- 5 days) through week 52. CNI will be stopped during the first belatacept infusion.
Arm Title
Calcineurin Inhibitor
Arm Type
Active Comparator
Arm Description
Patients randomized to this arm will remain on the current CNI as prescribed by post-transplant standard of care therapy.
Intervention Type
Drug
Intervention Name(s)
Belatacept
Other Intervention Name(s)
Nulojix
Intervention Type
Drug
Intervention Name(s)
Calcineurin Inhibitor
Other Intervention Name(s)
Prograf, Tacrolimus, Cyclosporine
Primary Outcome Measure Information:
Title
cGFR
Description
Serum creatinine will be checked at each study visit from which GFR will be calculated. 12 month 4 variable MDRD calculated GFR will be compared between the belatacept conversion group and the calcineurin inhibitor group.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Renal Histology
Description
Chronic Allograft Damage Index (CADI) and Interstitial Fibrosis/Tubular Atrophy (IFTA) renal pathology scores will be assessed by a local pathologist. CADI and IF/TA will be recorded at baseline (reperfusion biopsy) and at the 1 year protocol biopsy. The average progression of CADI and IF/TA will be compared in both groups and the average absolute CADI and IF/TA scores will be compared in both groups at 1 year post transplant.
Time Frame
12 months
Title
Biomarker profile
Description
The results of urine biomarkers (clusterin) will be correlated with the development of the primary and secondary endpoints in both groups. In this manner the investigators will be able to understand which genes/proteins are primarily altered by injury and assess how belatacept affects this process.
Time Frame
12 months
Title
Duration of Delayed (or slow) Graft Function
Description
The average duration of DGF/SGF will be compared in both belatacept and CNI groups
Time Frame
12 months
Title
Incidence of Acute Rejection
Description
Acute rejection by month 12 will be assessed by a local pathologist using the Banff 97 working classification of kidney transplant pathology. All biopsies will be interpreted locally for purposes of the study.
Time Frame
12 months
Title
New Onset Diabetes
Description
Subjects will be evaluated for post-transplant diabetes at visits after week 4.
Time Frame
12 months
Title
Blood Pressure Control
Description
Subjects are to be evaluated at each clinic visit to assess the need for adjustment of antihypertensive medication in order to achieve a BP of < 130/80 mmHg. Average systolic and diastolic blood pressure in both groups at Month 12, number of antihypertensive medications and change in intensity of hypertension treatment will be observed.
Time Frame
12 months
Title
Dyslipidemia
Description
Cholesterol levels in both groups, number of patients on dyslipidemic therapy at month 12 and change in intensity of dyslipidemia therapy will be observed
Time Frame
12 months
Title
Graft Survival
Description
Graft survival will be observed in both groups and compared at 12 months post-transplant
Time Frame
12 Months
Title
Patient survival
Description
Patient survival will be observed in both groups and compared at 12 months post-transplant
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Before any study procedures are performed, subjects will have the details of the study described to them, and they will be given a written informed consent document to read. Then, if subjects consent to participate in the study, they will indicate that consent by signing and dating the informed consent document in the presence of study personnel. All patients (> 18 years) who have received a deceased donor transplant and are at risk for SGF/DGF will be studied All gender and ethnicities will be considered in this study At risk for SGF/DGF is defined as: ECD (Extended Criteria Donor) donor kidney recipients ECD is defined as a donor over the age of 60 or age 50 to 60 with 2 of the following risk factors: Terminal creatinine > 1.5 mg/dL History of Hypertension Death due to cerebrovascular accident Donations after cardiac death (DCD) kidney recipients Donor organs with an actual cold ischemia time (CIT) > 19 hours Recipients of donor organs with a terminal creatinine > 1.5 mg/dL Only patients who receive Thymoglobulin induction and CNI maintenance at time of randomization will be considered for the study Men and women, 18 to 70 years of age Reproductive status: Definition of Women of Child-Bearing Potential (WOCBP). WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal. Post-menopause is defined as: Women who have had amenorrhea for >= 12 consecutive months (without another cause) and who have a documented serum follicle-stimulating hormone (FSH)level > 35 mIU/mL Women who have irregular menstrual periods and a documented serum FSH level > 35 mIU/mL Women who are taking hormone replacement therapy The following are WOCBP: Women using the following methods to prevent pregnancy: oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as intrauterine devices or barrier methods (diaphragm, condoms, spermicides). Women who are practicing abstinence Women who have a partner who is sterile (due to vasectomy) WOCBP must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours before the first dose of study drug. Women must not be breast-feeding Sexually active fertile men must use effective birth control if their partners are WOCBP Exclusion Criteria: Seronegative or unknown EBV (Epstein Barr Virus) serostatus (due to the risk of posttransplant lymphoproliferative disorder, PTLD) predominantly involving the central nervous system Patients with tuberculosis who have not been treated for latent infection Patients at high risk for polyoma virus-associated nephropathy, which is mostly due to BK virus infection Rejection episode before randomization Anatomic cause of SGF/DGF such as urinary leak, obstruction or thrombosis Patients with a prior or concurrent non-renal solid organ transplant Patients with living donor kidneys Patients with pediatric kidneys (age of less than 5 years) Dual kidney transplants (from the same donor) Immunologically high risk patients with a positive crossmatch pre- transplantation or donor specific antibody (DSA) > 5000 MFI ABO Incompatible transplantation Patients with HIV Subjects with any active infection or other contraindication that would normally exclude transplantation Patients with a history of malignancy in the last 5 years except non- melanoma skin cancer Baseline white blood cell count less than 2,000 Baseline hemoglobin less than 8 g/dL Patients with prior allergic reactions to belatacept Patients with prior allergic reactions to thymoglobulin Sex and Reproductive status - see WOCBP information in inclusion above Subjects currently receiving immunosuppressive agent(s) for other indications such as an autoimmune disease or subjects with comorbidities that treatment with such agents are likely during the trial. Subjects who have used any investigational drug within 30 days prior to the Day 1 visit Subjects previously treated with belatacept Prisoners or subjects who are involuntarily incarcerated Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Vinay Nair, D.O.
Phone
212-659-8086
Email
Vinay.Nair@mountsinai.org
First Name & Middle Initial & Last Name or Official Title & Degree
Brandy M Haydel, CCRC
Phone
212-241-0255
Email
Brandy.Haydel@mountsinai.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vinay Nair, D.O.
Organizational Affiliation
Icahn School of Medicine at Mount Sinai
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mount Sinai School of Medicine Recanati/Miller Transplantation Institute
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vinay Nair, D.O.
Phone
212-659-8086
Email
Vinay.Nair@mountsinai.org
First Name & Middle Initial & Last Name & Degree
Brandy Haydel, CCRC
Phone
212-241-0255
Email
Brandy.Haydel@mountsinai.org
First Name & Middle Initial & Last Name & Degree
Vinay Nair, D.O.
First Name & Middle Initial & Last Name & Degree
Sander Florman, MD
First Name & Middle Initial & Last Name & Degree
Peter Heeger, MD
First Name & Middle Initial & Last Name & Degree
Barbara Murphy, MD

12. IPD Sharing Statement

Learn more about this trial

Early Conversion From CNI to Belatacept in Renal Transplant Recipients With Delayed and Slow Graft Function

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