Belatacept Therapy for the Failing Renal Allograft (IM103-133)

The purpose of this study is to test the safety and effectiveness of belatacept (Nulojix®) in preventing antibody formation in patients with chronic failing kidney transplants. This study is a randomized study of first-time kidney transplant patients who have worsening kidney function and biopsy proven grade 2 or 3 interstitial fibrosis/tubular atrophy (IF/TA). Patients must be eligible to get a second transplant. They must have completed or be actively undergoing evaluation for re-listing for a second transplant. Patients will be randomized to either convert to belatacept or continue on calcineurin inhibitor-based therapy.

Study Overview

• Status: Completed
• Conditions: Failing Renal Allograft
• Intervention / Treatment: Drug: Belatacept; Drug: Mycophenolate mofetil; Drug: prednisone; Drug: Calcineurin inhibitor therapy

Detailed Description

The purpose of this study is to test the safety and effectiveness of the medicine belatacept (Nulojix®) in preventing antibodies from forming in people with a failing kidney transplant. Kidney transplant patients take immunosuppression medicines to prevent kidney rejection. When a kidney transplant begins to fail, the immunosuppression medicines are slowly weaned. Once dialysis is started, the immunosuppressant medicines are usually stopped. After immunosuppression is stopped, some people form antibodies. Antibodies are proteins that the immune system makes to protect against harmful foreign substances like bacteria, viruses, or foreign tissues, like a transplant. High levels of antibodies can make it harder to find a kidney donor for that person.

Participants will be randomized into one of the two treatment groups. One group will continue taking their current immunosuppression medicines. The people in the treatment group will be switched to belatacept (Nulojix®). Belatacept (Nulojix®) is an immunosuppression medicine that is approved by the U.S. Food and Drug Administration (the FDA) to prevent rejection in kidney transplant. Participants will stop taking calcineurin inhibitors (either cyclosporine or tacrolimus) or sirolimus but will keep taking other immunosuppression medicines like Cellcept (MMF) or azathioprine (Imuran) and prednisone. These medicines will be slowly weaned and will be stopped if the participant has to start dialysis. Participants will continue taking belatacept (Nulojix®), even while on dialysis.

The study team will test both groups to see how many people in each group develop antibodies.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed written informed consent
• Kidney transplant recipient (human leukocyte antigen (HLA) non-identical donor) who now has impaired renal allograft function with:
• Estimated glomerular filtration rate (GFR) < 35 with a decline in GFR of > 10% in the 12 months prior to enrollment and must have biopsy proven grade II or III interstitial fibrosis/tubular atrophy (IF/TA) OR
• Estimated GFR persistently < 20 ml/min over the 6 month period prior to enrollment absent other causes for graft dysfunction, and deemed to have a failing allograft by the patient's transplant nephrologist
• On a maintenance immunosuppressive regimen that includes calcineurin inhibitor (CNI)(tacrolimus or cyclosporine) or sirolimus and at least
• MMF of a dose of at least 1 gm/day or comparable dose of azathioprine OR
• Prednisone at a dose of at least 5 mg/day
• Men and women, ages 18 to 70, inclusive

Exclusion Criteria:

• Women of childbearing potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of study drug.
• Women who are pregnant or breastfeeding.
• Women with a positive pregnancy test.
• Sexually active fertile men not using effective birth control if their partners are WOCBP.
• Subjects who are Epstein-Barr Virus (EBV) seronegative.
• Subjects with any prior solid organ (e.g., heart, liver, pancreas) or cell (e.g., islet, bone marrow) transplant other than a renal allograft. Exception may be made for recipient of a simultaneous kidney-pancreas transplant who had previously experienced graft loss of the pancreas allograft due to thrombosis or rejection.
• Subjects with presence of donor specific antibody at the time of enrollment
• Subjects who have a recent history (within 1 yr) of biopsy proven acute rejection > Banff grade Ia
• Subjects who have a living donor identified for re-transplant within 3 months
• Subjects with a history of post-transplant lymphoproliferative disease (PTLD)
• Subjects at risk for tuberculosis (TB)
• Subjects with a history of cancer within the past 3 years, other than non-melanoma skin cancer(s)
• Subjects with a positive BK virus serum polymerase chain reaction (PCR) > 20,000 copies at the time of enrollment OR history of biopsy-proven BK nephropathy within the year prior to enrollment.
• Subjects with a mammogram that is suspicious for malignancy and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory, or other diagnostic evaluations
• Subjects who have difficult intravenous access or other reasons that would likely preclude the ability to receive long-term intravenous infusions
• Hypersensitivity to any medications that will be used in the protocol
• Subjects who have used any investigational drug within the 30 days prior to anticipated enrollment
• Subjects currently receiving belatacept as part of their maintenance immunosuppressive regimen
• Prisoners, or subjects who are involuntarily incarcerated.
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment; Belatacept (Nulojix) IV	Drug: Belatacept; Belatacept, dosing 10mg/kg- day 0, 2 weeks, 1 month, 2 months, 3 months; subsequent doses 5mg/kg monthly through duration of trial or until retransplantation, whichever is first.; Other Names: Nulojix; Drug: Mycophenolate mofetil; Continue current dose at enrollment. Upon initiation of dialysis, decrease dose by half, then discontinue 2 weeks later; Other Names: Cellcept; Drug: prednisone; Begin steroid withdrawal one month after initiation of dialysis, with monthly reduction in dose by half, with plans to discontinue prednisone by 3 months after initiation of dialysis; Other Names: Deltasone
ACTIVE_COMPARATOR: Control; Calcineurin inhibitor based therapy (cyclosporine or tacrolimus)	Drug: Mycophenolate mofetil; Continue current dose at enrollment. Upon initiation of dialysis, decrease dose by half, then discontinue 2 weeks later; Other Names: Cellcept; Drug: prednisone; Begin steroid withdrawal one month after initiation of dialysis, with monthly reduction in dose by half, with plans to discontinue prednisone by 3 months after initiation of dialysis; Other Names: Deltasone; Drug: Calcineurin inhibitor therapy; Upon enrollment, wean calcineurin inhibitor (CNI) to target tacrolimus trough of 3-5 nanogram/milliliter (ng/ml)or equivalent cyclosporine trough. Upon initiation of hemodialysis, discontinue CNI therapy over 5 days.; Other Names: tacrolimus; cyclosporine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Donor-specific Antibody Formation	The number of participants in each group with donor-specific antibody formation at 36 months following randomization.	Month 36

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glomerular Filtration Rate (GFR)	The glomerular filtration rate (GFR) assesses kidney function. GFR uses values for serum creatinine (SCr) measured in mg/dL, age in years, blood urea nitrogen (BUN) measures in mg/dL, and serum albumin (Alb) measured in g/dL. GFR is calculated as 170 x (SCr/0.95)^(-0.999) x (Age)^(-0.176) x (0.762 if the patient is female) x (1.180 if the patient is black) x (BUN)^(-0.170) x (Alb)^(0.318). A value of 90 or above is considered normal while values between 15 and 29 indicate severely decreased kidney function and values below 15 indicate kidney failure. The GFR in participants who do not require dialysis will be followed for two years.	Baseline up to Month 24
Time to Initiation of Dialysis	Time to dialysis is measured as the time of randomization to initiation of dialysis. Participants already requiring dialysis at the time of enrollment were excluded from this endpoint analysis.	Up to Year 2
Number of Participants With Anti-human Leukocyte Antigen (HLA) Alloantibodies	The presence of anti-HLA Class I and Class II alloantibodies is categorized as being negative (absent for both classes of alloantibodies), positive for Class I, positive for Class II, and positive for both Class I and Class II alloantibodies.	Baseline up to Month 36
Number of Infectious Complications	The number of infections complications occurring among study participants is presented here.	Baseline up to Month 36

Collaborators and Investigators

• Sponsor: Andrew B Adams
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Andrew B Adams, MD, PhD, Emory University

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (ACTUAL): December 12, 2019
• Study Completion (ACTUAL): December 12, 2019

Study Registration Dates

• First Submitted: August 9, 2013
• First Submitted That Met QC Criteria: August 9, 2013
• First Posted (ESTIMATE): August 13, 2013

Study Record Updates

• Last Update Posted (ACTUAL): January 26, 2021
• Last Update Submitted That Met QC Criteria: January 6, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Kidney transplant
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Immune Checkpoint Inhibitors; Antitubercular Agents; Antibiotics, Antitubercular; Prednisone; Tacrolimus; Mycophenolic Acid; Abatacept; Cyclosporine; Cyclosporins; Calcineurin Inhibitors
• Other Study ID Numbers: IRB00060470; IM103-133 (OTHER: Bristol-Myers Squibb)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No