Optimization of NULOJIX® Usage As A Means of Avoiding CNI and Steroids in Renal Transplantation

Phase 2

Terminated

• Conditions: Kidney Transplantation; Renal Transplantation
• Interventions: Drug: Alemtuzumab; Drug: MMF; Biological: Basiliximab; Biological: Belatacept; Drug: Short-term Tac; Drug: tacrolimus; Drug: methylprednisolone

• Registration Number: NCT01436305
• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary

The purpose of this study was to assess whether a new drug, Nulojix® (belatacept), would minimize serious long term side effects associated with anti-rejection medications while still protecting the new kidney from damage. The researchers also wanted to learn more about the safety of this treatment and long term health of the transplanted kidney.

Detailed Description

Dialysis or kidney transplant are the two ways to treat kidney failure. Transplant recipients have to take anti-rejection medications to prevent their immune system (the body's natural defense system against illness) from rejecting their new kidney. Most patients who undergo a kidney transplant must take these anti-rejection medications for the rest of their lives. Taking standard anti-rejection medications for a long time can cause serious side effects, including kidney damage. There would be a benefit to finding new anti-rejection medications that work just as well, but don't damage the kidney.

Study Timeline

• Study Start: 2011-09
• Study First Submitted: 2011-09-13
• Study First Submitted QC: 2011-09-15
• Study First Posted: 2011-09-19
• Primary Completion: 2015-04
• Study Completion: 2015-04
• Results First Submitted: 2016-11-10
• Results First Submitted QC: 2017-07-28
• Status Verified: 2017-08
• Last Update Submitted: 2017-08-29
• Results First Posted: 2017-08-30
• Last Update Posted: 2017-09-27

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 19

Inclusion Criteria

• Male or Female, 18-65 years of age at the time of enrollment;
• Ability to understand and provide written informed consent;
• Candidate for primary renal allograft from either a living or deceased-donor;
• No known contraindications to study therapy using NULOJIX® (belatacept);
• Female participants of childbearing potential must have a negative pregnancy test upon study entry;
• Female and male participants with reproductive potential must agree to use FDA approved methods of birth control during participation in the study and for 4 months following completion of the study;
• Flow-based PRA within last 12 months (in absence of a sensitizing event) of < 30% as determined by each participating study center. If the subject experienced a sensitizing event after the PRA test date, then the PRA must be repeated and confirmed <30%;
• Negative crossmatch or a PRA of 0% on historic and admission sera as determined by each participating study center.
• A documented negative TB test within the 12 months prior to transplant. If documentation is not present at the time of transplantation, and the subject does not have any risk factors for TB, a TB-specific interferon gamma release assay (IGRA) may be performed.

Exclusion Criteria

• Need for multi-organ transplant;
• Recipient of previous organ transplant;
• EBV sero-negative (or unknown) recipients;
• Active infection including hepatitis B, hepatitis C, or HIV;
• Individuals who have required treatment with prednisone or other immunosuppressive drugs within 1 year prior to transplant;
• Individuals undergoing transplant using organs from extended criteria donor (ECD) or donation after cardiac death (DCD) donors;
• HLA identical living donors;
• Individuals at significant risk of early recurrence of the primary renal disease including FSGS and MPGN type 2 or any other disease that in the opinion of the investigator is at increased likelihood of recurrence and which may result in rapid decline in renal function;
• Individuals previously treated with NULOJIX® (belatacept);
• Any condition that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements;
• Use of investigational drugs within 4 weeks of enrollment;
• Known hypersensitivity to mycophenolate mofetil (MMF) or any of the drug's components;
• Administration of live attenuated vaccine(s) within 8 weeks of enrollment.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tac maintenance	Alemtuzumab	Group 1 Study Therapy Regimen:Induction with alemtuzumab and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF). Campath® (alemtuzumab); long-term Prograf® (tacrolimus), or equivalent ; CellCept® (mycophenolate mofetil- MMF), or equivalent , and 4 day course of MEDROL® (methylprednisolone)
Tac maintenance	MMF	Group 1 Study Therapy Regimen:Induction with alemtuzumab and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF). Campath® (alemtuzumab); long-term Prograf® (tacrolimus), or equivalent ; CellCept® (mycophenolate mofetil- MMF), or equivalent , and 4 day course of MEDROL® (methylprednisolone)
Belatacept maintenance	Belatacept	Group 2 Study Therapy Regimen: Induction with alemtuzumab and maintenance with Nulojix® (belatacept) and mycophenolate mofetil (MMF). Campath® (alemtuzumab); Nulojix® (belatacept); CellCept® (mycophenolate mofetil- MMF), or equivalent, and 4 day course of MEDROL®(Methylprednisolone)
Belatacept maintenance	methylprednisolone	Group 2 Study Therapy Regimen: Induction with alemtuzumab and maintenance with Nulojix® (belatacept) and mycophenolate mofetil (MMF). Campath® (alemtuzumab); Nulojix® (belatacept); CellCept® (mycophenolate mofetil- MMF), or equivalent, and 4 day course of MEDROL®(Methylprednisolone)
Basiliximab induction/Short-term Tac	Basiliximab	Short term = 3 months Group 3 Study Therapy Regimen: Induction with 2 doses of basiliximab and tacrolimus for 84 days and maintenance with Nulojix® (belatacept) and mycophenolate mofetil (MMF). Simulect® (basiliximab); Nulojix® (belatacept); short-term course of Prograf® (tacrolimus), or equivalent; CellCept® (mycophenolate mofetil- MMF), or equivalent, and 4 day course of MEDROL® (methylprednisolone)
Basiliximab induction/Short-term Tac	Short-term Tac	Short term = 3 months Group 3 Study Therapy Regimen: Induction with 2 doses of basiliximab and tacrolimus for 84 days and maintenance with Nulojix® (belatacept) and mycophenolate mofetil (MMF). Simulect® (basiliximab); Nulojix® (belatacept); short-term course of Prograf® (tacrolimus), or equivalent; CellCept® (mycophenolate mofetil- MMF), or equivalent, and 4 day course of MEDROL® (methylprednisolone)
Basiliximab induction/Short-term Tac	Belatacept	Short term = 3 months Group 3 Study Therapy Regimen: Induction with 2 doses of basiliximab and tacrolimus for 84 days and maintenance with Nulojix® (belatacept) and mycophenolate mofetil (MMF). Simulect® (basiliximab); Nulojix® (belatacept); short-term course of Prograf® (tacrolimus), or equivalent; CellCept® (mycophenolate mofetil- MMF), or equivalent, and 4 day course of MEDROL® (methylprednisolone)
Tac maintenance	tacrolimus	Group 1 Study Therapy Regimen:Induction with alemtuzumab and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF). Campath® (alemtuzumab); long-term Prograf® (tacrolimus), or equivalent ; CellCept® (mycophenolate mofetil- MMF), or equivalent , and 4 day course of MEDROL® (methylprednisolone)
Belatacept maintenance	Alemtuzumab	Group 2 Study Therapy Regimen: Induction with alemtuzumab and maintenance with Nulojix® (belatacept) and mycophenolate mofetil (MMF). Campath® (alemtuzumab); Nulojix® (belatacept); CellCept® (mycophenolate mofetil- MMF), or equivalent, and 4 day course of MEDROL®(Methylprednisolone)
Belatacept maintenance	MMF	Group 2 Study Therapy Regimen: Induction with alemtuzumab and maintenance with Nulojix® (belatacept) and mycophenolate mofetil (MMF). Campath® (alemtuzumab); Nulojix® (belatacept); CellCept® (mycophenolate mofetil- MMF), or equivalent, and 4 day course of MEDROL®(Methylprednisolone)
Basiliximab induction/Short-term Tac	MMF	Short term = 3 months Group 3 Study Therapy Regimen: Induction with 2 doses of basiliximab and tacrolimus for 84 days and maintenance with Nulojix® (belatacept) and mycophenolate mofetil (MMF). Simulect® (basiliximab); Nulojix® (belatacept); short-term course of Prograf® (tacrolimus), or equivalent; CellCept® (mycophenolate mofetil- MMF), or equivalent, and 4 day course of MEDROL® (methylprednisolone)
Basiliximab induction/Short-term Tac	methylprednisolone	Short term = 3 months Group 3 Study Therapy Regimen: Induction with 2 doses of basiliximab and tacrolimus for 84 days and maintenance with Nulojix® (belatacept) and mycophenolate mofetil (MMF). Simulect® (basiliximab); Nulojix® (belatacept); short-term course of Prograf® (tacrolimus), or equivalent; CellCept® (mycophenolate mofetil- MMF), or equivalent, and 4 day course of MEDROL® (methylprednisolone)
Tac maintenance	methylprednisolone	Group 1 Study Therapy Regimen:Induction with alemtuzumab and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF). Campath® (alemtuzumab); long-term Prograf® (tacrolimus), or equivalent ; CellCept® (mycophenolate mofetil- MMF), or equivalent , and 4 day course of MEDROL® (methylprednisolone)

Primary Outcome Measures

Name	Time	Method
Mean Glomerular Filtration Rate (GFR) Calculated for Each Treatment Group Using the CKD-EPI Equation at Wk 52	Week 52	GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). A score of ≥ 90 means kidney function is normal. A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. Scores between 30 and 59 indicates moderately reduced kidney function. Scores between 15 and 29 indicate severely reduced kidney function. Scores below 15 indicate very severe or endstage kidney failure.

Secondary Outcome Measures

Name	Time	Method
Count of Participants With Biopsy Proven Acute Rejection at Any Time Post-Transplant	Transplantation through last study visit (up to week 156)	Biopsy proven acute rejection was defined as histologic evidence of borderline or higher cellular rejection per local pathologist.
Count of Participants With Estimated Glomerular Filtration Rate (GFR) < 60 mL/Min/1.73 m^2 by CKD EPI	Week 52, Week 104, and Week 156	GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). A score of ≥90 means kidney function is normal. A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. Scores between 30 and 59 indicates moderately reduced kidney function. Scores between 15 and 29 indicate severely reduced kidney function. Scores below 15 indicate very severe or endstage kidney failure. This measure specifically looked at participants with scores less than 60.
Count of Participants by Chronic Kidney Disease (CKD) Stage Post-Transplant	Week 52, Week 104, and Week 156	The stages of Chronic Kidney Disease are defined using the participant's GFR value as indicated below: Stage 1 if GFR value is ≥90; Stage 2 if GFR value is ≥60 and \< 90; Stage 3A if 45 ≤GFR \< 60; Stage 3B if 30 ≤ GFR \< 45; Stage 4 if 15 ≤GFR \< 30;l Stage 5 if GFR \< 15.; Stage 1 means kidney function is normal. Stage 2 indicates mildly reduced kidney function, pointing to kidney disease. Stages 3A and 3B indicate moderately reduced kidney function. Stage 4 indicates severely reduced kidney function. Stage 5 indicates very severe or end stage kidney failure.
Count of Participants With CKD Stage 4 or 5	Week 52, Week 104, and Week 156	The stages of Chronic Kidney Disease are defined using the participant's GFR value as indicated below.; Stage 1 if GFR value is ≥90; Stage 2 if 60 ≤ GFR \< 90; Stage 3A if 45 ≤ GFR \< 60; Stage 3B if 30 ≤ GFR \< 45; Stage 4 if 15 ≤ GFR \< 30; Stage 5 if GFR \< 15.; Stage 1 means kidney function is normal. Stage 2 indicates mildly reduced kidney function, pointing to kidney disease. Stages 3A abd 3B indicate moderately reduced kidney function. Stage 4 indicates severely reduced kidney function. Stage 5 indicates very severe or end stage kidney failure.
Mean Calculated eGFR Using MDRD 4 Variable Model	Week 52, Week 104, and Week 156	The estimated Glomerular Filtration Rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation (MDRD). A score of ≥90 means kidney function is normal. A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. Scores between 30 and 59 indicates moderately reduced kidney function. Scores between 15 and 29 indicate severely reduced kidney function. Scores below 15 indicate very severe or endstage kidney failure.
The Slope of eGFR by CKD-EPI Over Time Based on Serum Creatinine	Week 52, Week 104, and Week 156	The estimated Glomerular Filtration Rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). A score of ≥90 means kidney function is normal. A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease. Scores between 30 and 59 indicates moderately reduced kidney function. Scores between 15 and 29 indicate severely reduced kidney function. Scores below 15 indicate very severe or endstage kidney failure. An estimate of the slope, or change over time, in eGFR was produced using standard statistical linear modeling procedures. The estimate was then re-scaled so that it can be interpreted as a change in eGFR per month. Positive numbers indicate increasing kidney function. Larger numbers indicate greater change in kidney function.
Count of Participants With Delayed Graft Function Post-Transplant	Any time within the first week post-transplant	Delayed graft function is defined as dialysis in the first week on one or more occasions for any indication other than the treatment of acute hyperkalemia in the setting of otherwise acceptable renal function
An Increase of One or More Grades of CAN/IFTA When Comparing the Implantation and Subsequent Protocol Biopsies	Week 52, Week 104, and Week 156	CAN/IFTA grades reflect the severity of interstitial fibrosis and tubular atrophy present in the tissue obtained during a kidney biopsy. Higher grades indicate greater severity in interstitial fibrosis and tubular atrophy present the kidney biopsy tissue. The aim of this measure was to compare central lab reviewed pre-implantation biopsies to post-transplant biopsies, as pre-specified per protocol; however, the central lab had an inadequate set of biopsies to proceed with evaluation.
Count of Participants With CAN/IFTA Grade I, II or III at Any Time Post-transplant	Transplantation through last study visit (up to week 156)	CAN/IFTA grades were determined per local pathology interpretations of biopsy tissue. These grades reflect the severity of interstitial fibrosis and tubular atrophy present in the tissue obtained during a kidney biopsy. Higher grades indicate greater severity in interstitial fibrosis and tubular atrophy present the kidney biopsy tissue.
Count of Participants With Acute Cellular Rejection Grade Equal to or Greater Than IA, by the Banff 2007 Criteria	Transplantation through last study visit (up to week 156)	Acute cellular rejection is when lesions at the site of the graft characteristically are infiltrated with large numbers of lymphocytes and macrophages that cause tissue damage. Acute cellular rejection for this endpoint is defined as a grade ≥ IA by Banff 2007 criteria.
Count of Participants by Severity of First Acute Cellular Rejection by Wk 52	Transplantation through Week 52	Acute cellular rejection is when lesions at the site of the graft characteristically are infiltrated with large numbers of lymphocytes and macrophages that cause tissue damage. Acute cellular rejection for this endpoint is defined as a grade ≥ IA by Banff 2007 criteria. Severity is graded as IA, IB, IIA, IIB, or III, with IA being the mildest form of cellular rejection and III being the most severe form of cellular rejection. Originally, this endpoint was worded as "The severity of first and highest acute cellular rejection within the first 52 weeks." But since the highest grade for each subject coincided with the first ACR episode for each subject, only a summary of severity of the first episode is presented here.
Count of Participants With Antibody Mediated Rejection	Transplantation through last study visit (up to week 156)	Antibody mediated rejection (AMR) is defined as diffusely positive staining for C4d, presence of circulating anti-donor antibodies and morphologic evidence of acute tissue injury.
Type of Treatment of Rejection	Transplantation through last study visit (up to week 156)	Upon having a biopsy performed, persons often receive treatment for rejection based on the results of the biopsy, which may or may not have shown signs of rejection. Details of biopsy findings and corresponding treatment are presented here for each instance of treatment for rejection. Acronyms and abbreviations are defined below.; ACR=Acute Cellular Rejection ATG=Anti-thymocyte globulin therapy Chr. AMR=Chronic Antibody Mediated Rejection Gd.=Grade IFTA=Interstitial Fibrosis and Tubular Atrophy IVIG=Intravenous Immunoglobulin therapy.; Only 'for cause' biopsies were performed post-transplant; thus, it is possible for a participant to be included in the analysis population and not have a biopsy for this outcome measure.
Count of Participants With de Novo Anti-donor HLA Antibodies at Wk 52	Week 52	The presence of antibodies reactive to Histocompatibility Antigen (HLA) molecules expressed on the renal allograft have been associated with both acute and chronic injury to the transplanted kidney. The development of de novo anti- donor HLA antibodies may mean a person is more likely to reject the graft.
Count of Participants With Either New Onset Diabetes After Transplant (NODAT) or Impaired Fasting Glucose (IFG) at Wk 52 Based on Criteria Specified by the ADA and WHO	Week 52	New onset diabetes is the development of diabetes post-kidney transplant. It was identified by the clinical sites caring for each participant and reported directly in the clinical database. Impaired fasting glucose (IFG) is a determination made by referencing glucose measurements obtained from a standard chemistry panel. Any fasting glucose measure that is between 110 and 125 mg/dL is classified as IFG.; Acronyms: American Diabetes Association (ADA); World Health Organization (WHO).
Count of Participants With Treated Diabetes Between Day 14 and Wk 52	Day 14 to Week 52	Treated diabetes is defined as the receipt of oral medication or insulin for \>14 days between 14 days and 52 weeks post-transplant
HbA1c Measured at Days 28 & 84, and Weeks 24, 36, 52, 72, 104 and 156	Day 28, Day 84, Week 24, Week 36, Week 52, Week 72, Week 104, Week 156	Hemoglobin A1c (HbA1c) measures the average blood glucose levels over 8-12 weeks, thus acting as a useful long-term gauge of blood glucose control. A value below 6.0% reflects normal levels, 6.0% to 6.4% reflects prediabetes, and a value of ≥ 6.5% reflects diabetes.
Standardized Blood Pressure Measurement at Wk 52	Week 52	A blood pressure measurement consists of two numbers: the systolic and diastolic pressures. Systolic pressure measures the pressure in blood vessels when the heart beats. Diastolic pressure measures the pressure in blood vessels between beats of the heart. Systolic measures of \<120 and diastolic measures of \<80 are considered normal. Systolic measures of 120-139 and diastolic measures of 80-89 are considered at risk (or pre-hypertension). Systolic measures of ≥140 and diastolic measures of ≥90 are considered high.
Count of Participants With Use of Anti-hypertensive Medications at Wk 52	Week 52	Anti-hypertensive medications are a class of drugs that are used to treat hypertension. The medications seek to prevent the complications of high blood pressure, such as stoke and myocardial infarction.
Fasting Lipid Profile (Total Cholesterol, Non-HDL Cholesterol, LDL, HDL, and Triglyceride) at Baseline and Wks 24, 52, 104 and 156	Baseline, Week 24, Week 52, Week 104, Week 156	A fasting lipid profiles measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. These measurements are used in assessing one's risk of cardiovascular disease. Target ranges for each of these measures are detailed below.; Total cholesterol: 75-169 mg/dL if age ≤ 20; 100-199 mg/dL if age ≥ 21; high values indicate risk of cardiovascular disease; LDL cholesterol: \<70 mg/dL for people with documented cardiovascular disease or metabolic syndrome; \<100 mg/dL for people considered high risk for cardiovascular disease; \<130 mg/dL for people considered low risk for cardiovascular disease; high values indicate risk of cardiovascular disease; HDL cholesterol: 40mg/dL and higher; high values indicate reduced risk of cardiovascular disease; Non-HDL cholesterol: 30 mg/dL above the target value for LDL cholesterol; high values indicate risk of cardiovascular disease; Triglycerides: \<150 mg/dL; high values indicate risk of cardiovascular disease
Count of Participants With Use of Lipid Lowering Medications at Baseline and Wks 24, 52, 104 and 156	Baseline, Week 24, Week 52, Week 104, Week 156	Lipid lowering medications are used in the treatment of high levels of fats (lipids), such as cholesterol in blood
Total Daily Prescribed Pill Number at Days 28 and 84, and Wks 24, 36, 52, 72, 104 and 156	Day 28, Day 84, Week 24, Week 36, Week 52, Week 72, Week 104, Week 156	This is a measure of the total number of pills a participant was prescribed on a given day
Number of Events of Death or Graft Loss	Transplantation through last study visit (up to week 156)	This measure counts deaths and graft loss occurring at any point post transplantation. Graft loss is defined as need for dialysis for greater than 30 days duration, allograft nephrectomy, or retransplantation.
Count of Participants With Rejection	Transplantation through last study visit (up to week 156)	The number of participants who were treated by their local physician for any type of rejection including, but not limited to cellular rejection and antibody- mediated rejection of the transplanted kidney regardless of the presence of a biopsy.
Number of All Adverse Events (AEs) and Serious Adverse Events (SAEs)	Enrollment through last study visit (up to week 156)	Adverse events were collected systematically from enrollment through last study visit. Displayed below are counts of all adverse events per treatment group (including both serious and non-serious adverse events). Separately counts of all adverse events determined to be serious are displayed per treatment group. More detail about adverse events for this trial is displayed in the 'Adverse Event' section.
Count of Participants With Infections Requiring Hospitalization or Systemic Therapy Reported as Serious Adverse Events	Transplantation through last study visit (up to week 156)	Infections of certain types (i.e., excluding those identified in the protocol as occurring commonly in this study population) were required to be reported as a serious adverse event if they required either inpatient hospitalization of prolongation of a current hospitalization.
Count of Participants With BKV and CMV Viremia (Local Center Monitoring) Reported as Adverse Events	Transplantation through last study visit (up to week 156)	Viral infections following renal transplantation is significant source of recipient morbidity and mortality, and a significant cause of allograft dysfunction and loss. Specific viruses were monitored during this study using participant blood samples.; Acronyms: BK Polyoma Virus (BKV); Cytomegalovirus (CMV).
Count of Participants With EBV Infection as Reported on the Case Report Form as Adverse Events	Transplantation through last study visit (up to week 156)	Viral infections following renal transplantation is a significant source of recipient morbidity and mortality, and a significant cause of allograft dysfunction and loss. Specific viruses were monitored during this study using participant blood samples.; Acronym: Epstein-Barr virus (EBV)
Count of Participants With Fever > 39 Degrees Celsius and Blood Pressure < 90mm Hg Within 24 Hours of Onset of Transplant Procedure	24 hours after transplantation	Temperature of \>39 degrees Celsius would be an indication of fever most often in response to an infection or illness. Systolic blood pressure \<90mm Hg would be an indication of low blood pressure.

Trial Locations

Locations (3)

University of Alabama; 🇺🇸 Birmingham, Alabama, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

University of California San Francisco; 🇺🇸 San Francisco, California, United States