Safety and Efficacy of a Steroid-free, Calcineurin Inhibitor-free, Belatacept-based Immunosuppressive Regimen

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Collaborator:
Clinical Trials in Organ Transplantation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01856257
First received: May 14, 2013
Last updated: September 6, 2013
Last verified: September 2013
  Purpose

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 get a kidney transplant must take these anti-rejection medications for the rest of their lives, or for as long as the kidney continues to work. 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.

The purpose of this study is to find out if NULOJIX® (belatacept), will minimize serious long term side effects seen with anti-rejection medications while still protecting your new kidney from damage. The researchers also want to learn more about the safety of this treatment and long term health of your transplanted kidney.


Condition Intervention Phase
Kidney Transplantation
Transplantation
Biological: Anti-thymocyte Globulin (Rabbit)
Biological: Belatacept
Drug: Methylprednisolone
Biological: Basiliximab
Drug: Mycophenolate Mofetil
Drug: Tacrolimus
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Steroid and Tacrolimus Avoidance Using NULOJIX® (Belatacept) in Renal Transplantation (CTOT-16)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Mean estimated glomerular filtration rate (eGFR) calculated for each treatment group using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) [ Time Frame: week 52 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • The incidence of clinically suspected and biopsy proven acute rejection within the first 52 weeks as defined by histologic evidence of rejection and graft dysfunction. [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • Proportion of subjects with estimated Glomerular Filtration Rate (eGFR) < 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • Change in chronic kidney disease (CKD) stages from baseline. [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]

    Chronic kidney disease (CKD) stages are defined as follows:

    • Stage 1: glomerular filtration rate (GFR) of 90+ (normal kidney function but urine findings or structural abnormalities or genetic trait point to kidney disease)
    • Stage 2: GFR of 60-89 (mildly reduced kidney function point to kidney disease)
    • Stage 3A: GFR of 45-59 (moderately reduced kidney function)
    • Stage 3B: GFR of 30-44 (moderately reduced kidney function)
    • Stage 4: GFR of 15-29 (severly reduced kidney function)
    • Stage 5: GFR of <15 (very severe, or endstage kidney failure)

  • Proportion of subjects with defined chronic kidney disease (CKD) stage 4 or 5. [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • Mean calculated estimated glomerular filtration rate (eGFR) using modification of diet in renal disease (MDRD) 4 variable model. [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • The slope of estimated glomerular filtration Rate (eGFR) by chronic kidney disease epidemiology collaboration equation (CKD-EPI) over time based on serum creatinine collected at all visits indicated on the schedule of events [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • The incidence of delayed graft function [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
    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

  • The incidence of acute cellular rejection grade equal to or > than IA, by the Banff 2007 criteria, within the first 52 weeks. [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • The severity of first and highest grade of acute cellular rejection within the first 52 weeks [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • The incidence of antibody mediated rejection [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
    Antibody mediated rejection is defined as diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury.

  • The type of treatment of rejection. [ Time Frame: week 52 ] [ Designated as safety issue: No ]
    The concomitant medications or therapies to treat the participant's rejection will be summarized by the adverse reaction outcome status. Medications will be defined by each site's standard of care.

  • The prevalence of de novo anti-donor histocompatibility antigen (HLA) antibodies [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • The incidence of new onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG)based on criteria specified by the ADA and WHO [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • The incidence of treated diabetes between day 14 and week 52 [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
    Treated diabetes is defined as receipt of any oral medication or insulin for the treatment of diabetes for >14 days.

  • Hemoglobin A1c (HbA1c) measurements [ Time Frame: baseline, days 28 & 84, and weeks 28, 36 and 52 ] [ Designated as safety issue: No ]
  • Standardized blood pressure measurement and use of anti-hypertensive medications [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • Fasting lipid profile (total cholesterol, non-high density lipoprotein cholesterol, low-density lipoprotein, high density lipoprotein, and triglyceride) and use lipid lowering medications [ Time Frame: baseline and 28 and 52 weeks ] [ Designated as safety issue: No ]
  • Total daily prescribed pill count [ Time Frame: days 28 and 84 and weeks 28, 36 and 52 ] [ Designated as safety issue: No ]
  • The incidence of death or graft loss. [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • The incidence of rejection. [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • The incidence of all adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • The incidence of infections requiring hospitalization, or systemic therapy [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • The incidence of BK Polyoma Virus (BKV) and Cytomegalovirus (CMV) viremia (local center monitoring) [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • The incidence of Epstein Barr Virus (EBV) infection as reported on the case report form [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • The incidence fever > 39 degrees and blood pressure < 90mm Hg within 24 hours of onset of transplant procedure [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 180
Study Start Date: July 2013
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Thymoglobulin + tacrolimus + MMF
Induction with Thymoglobulin, methylprednisolone, and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF)
Biological: Anti-thymocyte Globulin (Rabbit)
The target dosage is 6mg/kg total over 3 to 4 days. The recommended route of administration is intravenous infusion using a high-flow vein.
Other Name: Thymoglobulin
Drug: Methylprednisolone
Methylprednisolone will be administered at a target dose of 500 mg beginning on the day of transplant, and tapered to 250 mg day 1 post-transplant, 125 mg day 2 post-transplant, 60 mg day 3 post-transplant, 30 mg day 4 post-transplant and day 5 post-transplant 0 mg if therapeutic tacrolimus level achieved for groups 1 and 3.
Other Name: Medrol
Drug: Mycophenolate Mofetil
Mycophenolate Mofetil will be administered at a target dose of 1000 mg orally twice a day. Myfortic® (mycophenolate sodium) may be used as a replacement for MMF. Mycophenolate sodium will be dosed at 720 mg PO BID. Mycophenolate sodium will be adjusted based on clinical complications.
Other Names:
  • CellCept®
  • MMF
  • Mycophenolate
  • Mycophenolate sodium
Drug: Tacrolimus
The site investigator will identify a starting tacrolimus dose at their discretion, in order to achieve the target trough levels, no later than 5 days post-transplantation. The dose will be adjusted to 5-8ng/ml for the active comparator arm (thymoglobulin + tacrolimus + MMF arm) or tapered off in the experimental arm (basiliximab + 20 weeks of tacrolimus + MMF + belatacept).
Other Name: Prograf
Experimental: Thymoglobulin + belatacept + MMF
Induction with Thymoglobulin, methylprednisolone, and maintenance with belatacept and mycophenolate mofetil (MMF)
Biological: Anti-thymocyte Globulin (Rabbit)
The target dosage is 6mg/kg total over 3 to 4 days. The recommended route of administration is intravenous infusion using a high-flow vein.
Other Name: Thymoglobulin
Biological: Belatacept
Participants will receive belatacept at a dose of 10mg/kg up on day 1, 5, 14, 28, 56 and 84. After 84 days, subjects will receive a maintenance dose of 5 mg/kg every 4 weeks until completion of the trial.
Other Name: NULOJIX
Drug: Methylprednisolone
Methylprednisolone will be administered at a target dose of 500 mg beginning on the day of transplant, and tapered to 250 mg day 1 post-transplant, 125 mg day 2 post-transplant, 60 mg day 3 post-transplant, 30 mg day 4 post-transplant and day 5 post-transplant 0 mg if therapeutic tacrolimus level achieved for groups 1 and 3.
Other Name: Medrol
Drug: Mycophenolate Mofetil
Mycophenolate Mofetil will be administered at a target dose of 1000 mg orally twice a day. Myfortic® (mycophenolate sodium) may be used as a replacement for MMF. Mycophenolate sodium will be dosed at 720 mg PO BID. Mycophenolate sodium will be adjusted based on clinical complications.
Other Names:
  • CellCept®
  • MMF
  • Mycophenolate
  • Mycophenolate sodium
Experimental: Basiliximab + 20 weeks of tacrolimus + MMF + belatacept
Induction with 2 doses of basiliximab, methylprednisolone, plus tacrolimus for 20 weeks and maintenance with belatacept and mycophenolate mofetil (MMF). Subjects participating in this arm may have tacrolimus reinstated, at a dose to be determined by the site investigator, if any of the following events occur: 1 - An acute rejection episode 2- Request of the subject or site Investigator.
Biological: Belatacept
Participants will receive belatacept at a dose of 10mg/kg up on day 1, 5, 14, 28, 56 and 84. After 84 days, subjects will receive a maintenance dose of 5 mg/kg every 4 weeks until completion of the trial.
Other Name: NULOJIX
Drug: Methylprednisolone
Methylprednisolone will be administered at a target dose of 500 mg beginning on the day of transplant, and tapered to 250 mg day 1 post-transplant, 125 mg day 2 post-transplant, 60 mg day 3 post-transplant, 30 mg day 4 post-transplant and day 5 post-transplant 0 mg if therapeutic tacrolimus level achieved for groups 1 and 3.
Other Name: Medrol
Biological: Basiliximab
Basiliximab will be administered in two doses of 20 mg each.
Other Name: Simulect
Drug: Mycophenolate Mofetil
Mycophenolate Mofetil will be administered at a target dose of 1000 mg orally twice a day. Myfortic® (mycophenolate sodium) may be used as a replacement for MMF. Mycophenolate sodium will be dosed at 720 mg PO BID. Mycophenolate sodium will be adjusted based on clinical complications.
Other Names:
  • CellCept®
  • MMF
  • Mycophenolate
  • Mycophenolate sodium
Drug: Tacrolimus
The site investigator will identify a starting tacrolimus dose at their discretion, in order to achieve the target trough levels, no later than 5 days post-transplantation. The dose will be adjusted to 5-8ng/ml for the active comparator arm (thymoglobulin + tacrolimus + MMF arm) or tapered off in the experimental arm (basiliximab + 20 weeks of tacrolimus + MMF + belatacept).
Other Name: Prograf

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or Female, 18-65 years of age at the time of enrollment;
  2. Ability to understand and provide written informed consent;
  3. Candidate for primary renal allograft from either a living or deceased donor;
  4. No known contraindications to study therapy using NULOJIX® (belatacept);
  5. Female participants of childbearing potential must have a negative pregnancy test upon study entry;
  6. Participants with reproductive potential must agree to use an appropriate method(s) of birth control as outlined in the CellCept® , Myfortic® or generic package labeling during participation in the study and for 4 months following completion of the study;
  7. No donor specific antibodies prior to transplant that are considered to be of clinical significance by the site investigator;
  8. Negative crossmatch or a PRA of 0% on historic and current sera, as determined by each participating study center.
  9. A documented negative TB test within the 6 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:

  1. Need for multi-organ transplant
  2. Recipient of previous organ transplant
  3. Epstein Barr Virus (EBV) sero-negative (or unknown) recipients
  4. Active infection including hepatitis B, hepatitis C, or human Immunodeficiency Virus (HIV)
  5. Individuals who have required treatment with prednisone or other immunosuppressive drugs within 1 year prior to transplant
  6. Individuals undergoing transplant using organs from extended criteria donor (ECD) or donation after cardiac death (DCD) donors
  7. Histocompatibility antigen (HLA) identical living donors
  8. Individuals at significant risk of early recurrence of the primary renal disease including focal segmental glomerulosclerosis (FSGS) and membranoproliferative glomerulonephritis (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
  9. Known history of thrombotic events or risk factors; including any of the following:

    1. Factor V Leiden, elevated homocysteine, positive lupus anticoagulant, elevated anticardiolipin antibody, heparin induced thrombocytopenia
    2. A family history of a heritable thrombotic condition,
    3. Recurrent DVT or PE,
    4. Unexplained stillborn infant or recurrent spontaneous abortion or other congenital or acquired thrombotic disorder At the discretion of the investigator, a history of thrombosis of a dialysis access graft, fistula, or indwelling catheter/device may not be considered an exclusion criterion
  10. Any condition that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements
  11. Use of investigational drugs within 4 weeks of enrollment
  12. Known hypersensitivity to mycophenolate mofetil (MMF)or any of the drug's components
  13. Administration of live attenuated vaccine(s) within 8 weeks of enrollment
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01856257

Locations
United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Deana Mays    205-934-0035    dmays@uab.edu   
Principal Investigator: Roslyn Mannon, MD         
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: JoAnn Zlatunich    415-353-8380    Joann.zlatunich@ucsfmedctr.org   
Principal Investigator: Peter Stock, MD, PhD         
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Keshawna Shere    404-712-1737      
Contact       Keshawna.sherer@emoryhealthcare.org   
Principal Investigator: Kenneth Newell, MD, PhD         
Sponsors and Collaborators
Clinical Trials in Organ Transplantation
Investigators
Principal Investigator: Kenneth Newell, MD, PhD Emory University
Study Chair: Roslyn B. Mannon, M.D. University of Alabama at Birmingham
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01856257     History of Changes
Other Study ID Numbers: DAIT CTOT-16
Study First Received: May 14, 2013
Last Updated: September 6, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Kidney Transplantation
Transplantation
NULOJIX
belatacept
Transplantation, renal

Additional relevant MeSH terms:
Antilymphocyte Serum
Mycophenolate mofetil
Tacrolimus
Basiliximab
Abatacept
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Mycophenolic Acid
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Anti-Inflammatory Agents
Therapeutic Uses
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal

ClinicalTrials.gov processed this record on August 27, 2014