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Open-Label Phase 2 Trial of a Steroid-Free, CNI-Free, Belatacept-Based Immunosuppressive Regimen

This study has been terminated.
(Safety concern:rejection rate disparity between investigational versus control arm. Stopping rule not met.)
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: June 21, 2016
Last verified: June 2016
  Purpose
The primary objective is to evaluate a NULOJIX® (belatacept) based regimens as a means of improving long-term graft function without increasing the risks of immunologic graft injury by avoiding both calcineurin inhibitors (CNIs) and corticosteroids.

Condition Intervention Phase
Primary Renal Allograft Candidate
Kidney 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) By Treatment Group Using the Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI) [ Time Frame: week 52 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Incidence of Clinically Suspected and Biopsy Proven Acute Rejection Within the first 52 Weeks-Defined by Histologic Evidence of Rejection and Graft Dysfunction [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • Proportion of Subjects with eGFR < 60 mL/min/1.73 m^2 by CKD-EPI [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • Change in Chronic Kidney Disease (CKD) Stages [ Time Frame: Baseline, week 52 ] [ Designated as safety issue: Yes ]

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

    • Stage 1: 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 (severely reduced kidney function)
    • Stage 5: GFR of <15 (very severe, or endstage kidney failure)

  • Proportion of Subjects with Defined CKD stage 4 or 5 [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • Mean Calculated eGFR Using Modification of Diet in Renal Disease (MDRD) 4 Variable Model [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • Slope of eGFR by CKD-EPI Over Time Based on Serum Creatinine [ Time Frame: week 52 ] [ Designated as safety issue: No ]
    Collection schedule per protocol's schedule of events.

  • Incidence of Delayed Graft Function [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
    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.

  • Incidence of Acute Cellular Rejection >/= IA Within the First 52 Weeks [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
    Using Banff 2007 criteria

  • Severity of First and Highest Grade of Acute Cellular Rejection Within the First 52 Weeks [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • Incidence of Antibody-Mediated Rejection [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
    Defined by diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury.

  • Type of Treatment of Rejection [ Time Frame: week 52 ] [ Designated as safety issue: No ]
    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.

  • Prevalence of De Novo Anti-Donor Histocompatibility Antigen (HLA) Antibodies [ Time Frame: week 52 ] [ Designated as safety issue: No ]
  • Incidence of New Onset Diabetes Post-Transplant (NODAT) or Impaired Fasting Glucose (IFG) [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
    Based ADA (American Diabetes Association) and WHO (World Health Organization) Criteria.

  • Incidence of Treated Diabetes Between Day 14 and Week 52 [ Time Frame: Day 14, 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 and 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 and Use of Lipid Lowering Medications [ Time Frame: Baseline,weeks 28 and 52 ] [ Designated as safety issue: No ]
    Total cholesterol, non-high density lipoprotein cholesterol, low-density lipoprotein, high density lipoprotein, and triglyceride.

  • Total Daily Prescribed Pill Count [ Time Frame: Days 28 and 84 and weeks 28, 36 and 52 ] [ Designated as safety issue: No ]
  • Incidence of Death or Graft Loss [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • Incidence of Rejection [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • Incidence of Infections Requiring Hospitalization or Systemic Therapy [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • Incidence of BK Polyoma Virus (BKV) and Cytomegalovirus (CMV) Viremia (local center monitoring) [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
  • Incidence of Epstein Barr Virus (EBV) Infection [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]
    As reported on the case report form

  • Incidence of Fever > 39 Celsius (102.2 Fahrenheit) degrees and Blood Pressure < 90mm Hg Within 24 Hours of Onset of Transplant Procedure [ Time Frame: week 52 ] [ Designated as safety issue: Yes ]

Enrollment: 69
Study Start Date: July 2013
Study Completion Date: April 2016
Primary Completion Date: April 2016 (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 Names:
  • Thymoglobulin®
  • ATG (Rabbit)
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:
  • MMF
  • CellCept®
  • mycophenolate acid
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 Names:
  • Thymoglobulin®
  • ATG (Rabbit)
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:
  • MMF
  • CellCept®
  • mycophenolate acid
Experimental: Basiliximab+20 weeks of tacrolimus+MMF + belatacept

Induction basiliximab and methylprednisolone, administration of NULOJIX® (belatacept) 24 hours post reperfusion (+/-12 hrs); maintenance immunosuppression with 1. )20 week course of Prograf® (tacrolimus) or equivalent 2.) CellCept® (mycophenolate mofetil- MMF), or Myfortic® (mycophenolate sodium), or equivalent.

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:
  • MMF
  • CellCept®
  • mycophenolate acid
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®

Detailed Description:

Taking standard anti-rejection medications for a long time can cause serious side effects, including kidney damage. 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 receive 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.

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

  Eligibility

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

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 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;
  • 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;
  • No donor specific antibodies prior to transplant that are considered to be of clinical significance by the site investigator;
  • Negative crossmatch or Panel Reactive Antibodies (PRA) of 0% on historic and current sera, as determined by each participating study center;
  • A documented negative tuberculosis (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:

  • Need for multi-organ transplant;
  • Recipient of previous organ transplant;
  • Epstein-Barr Virus (EBV) seronegative (or unknown) recipients;
  • Active infection including hepatitis B, hepatitis C, or human Immunodeficiency Virus (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;
  • Histocompatibility antigen (HLA) identical living donors;
  • 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;
  • Known history of thrombotic events or risk factors, including any of the following:

    • Factor V Leiden, elevated homocysteine, positive lupus anticoagulant, elevated anticardiolipin antibody, heparin-induced thrombocytopenia,
    • A family history of a heritable thrombotic condition,
    • Recurrent deep vein thrombosis (DVT) or pulmonary emboli (PE),
    • 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.

  • 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;
  • Blood type A2 and A2B donors into blood type B recipients.
  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
Birmingham, Alabama, United States, 35294
United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
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:
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: June 21, 2016
Health Authority: United States: Federal Government
United States: Data and Safety Monitoring Board
United States: Food and Drug Administration
United States: Institutional Review Board

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

Additional relevant MeSH terms:
Tacrolimus
Mycophenolate mofetil
Basiliximab
Antilymphocyte Serum
Abatacept
Mycophenolic Acid
Antibodies, Monoclonal
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antineoplastic Agents
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on September 29, 2016