Study of Belatacept in Subjects Who Are Undergoing a Renal Transplant

Lead sponsor

Bristol-Myers Squibb is the lead sponsor of 1,538 studies on the registry; 116 are open to participants now.

Of its 429 completed or terminated interventional studies of FDA-regulated products, 223 (52%) have results posted.

Study arms

• Active comparator
  Cyclosporin A

  Drug: Cyclosporin A

• Experimental
  Belatacept Less Intensive Regimen (LI)

  Drug: Belatacept Less Intensive Regimen (LI)

• Experimental
  Belatacept More Intensive Regimen (MI)

  Drug: Belatacept More Intensive Regimen (MI)

Interventions

• DrugCyclosporin A

  tablet, oral, 1st month target: 150-300 ng/mL, after 1st month target: 100-250 ng/mL, daily, 36 months, 100-250 ng/mL, daily, 84 months

  Also known as: CsA

• DrugBelatacept Less Intensive Regimen (LI)

  solution, IV, 10mg/kg: Days 1 and 5, Weeks 2, 4, 8 and 12, then 5 mg/kg every 4 weeks, q 4 weeks, 36 months months, 5 mg/kg every 4 weeks, q 4 weeks, 84 months

• DrugBelatacept More Intensive Regimen (MI)

  solution, IV, 10mg/kg: Days 1 and 5, Weeks 2, 4, 6, 8, 10,12, 16, 20, and 24, then 5 mg/kg every 4 weeks, q 4 weeks, 36 months, 5 mg/kg every 4 weeks, q 4 weeks, 84 months

Primary outcomes

1. Percentage of Participants Who Survived With a Graft at 12 Months Post-Transplant

   Participant and graft survival at 12 months was summarized within each treatment group. Graft loss was defined as either functional loss or physical loss (nephrectomy). Functional loss was defined as a sustained level of serum creatinine ≥ 6.0 mg/dL (530 μmol/L) as determined by central laboratory for ≥4 weeks or 56 or more consecutive days of dialysis.

   Time frame: Month 12 post-transplant

2. Percentage of Participants With a Measured Glomerular Filtration Rate (GFR) <60 mL/Min Per 1.73 m^2 at Month 12 or a Decrease in Measured GFR >=10 mL/Min Per 1.73 m^2 From Month 3 to Month 12

   GFR was assessed using a true measure of glomerular filtration via non-radiolabeled iothalamate clearance test using a validated procedure.

   Time frame: From Month 3 to Month 12

Secondary outcomes

1. Measured Glomerular Filtration Rate (GFR) by Month 12 and 24

   GFR was assessed using a true measure of glomerular filtration via nonradiolabeled iothalamate clearance test using a validated procedure. Missing measured GFR assessments were imputed. Here, 'n' signifies the number of evaluable participants for the reporting arm at the given time point. Missing measured GFR assessments were imputed to a GFR of zero.

   Time frame: At Month 12 and Month 24

2. Percentage of Participants With Chronic Allograft Nephropathy (CAN) at Month 12

   Biopsy-proven CAN was determined by a blinded central histopathologist using the Banff 97 working classification of kidney transplant pathology. Onset of CAN was determined by the biopsy date when it was observed. Participants were considered as having CAN at 12 months if: CAN observed in a biopsy either prior to 12 months (including baseline biopsy) or first post 12 months biopsy; Participant had graft loss during the first year post transplant; no biopsy available post 12 months and CAN not observed in biopsies prior to 12 months; no biopsy available either prior to or post 12 months; and the measured glomerular filtration rate from Month 3 to Month 12 decreases at least 10 mL/min/1.73m\^2. All other participants with missing 12 month biopsy were considered having no CAN observed at 12 months.

   Time frame: At Month 12

3. Percentage of Participants Who Survived With a Graft at 24 and 36 Months Post-Transplant

   Participant and graft survival at 12 months was summarized within each treatment group. Graft loss was defined as either functional loss or physical loss (nephrectomy). Functional loss will be defined as a sustained level of serum creatinine ≥ 6.0 mg/dL (530 μmol/L) as determined by central laboratory for ≥ 4 weeks or 56 or more consecutive days of dialysis.

   Time frame: Month 24 and Month 36 post-transplant

4. Calculated Glomerular Filtration Rate (GFR) at 6, 12, 24, 36 and 84 Months

   GFR was assessed using a true measure of glomerular filtration via nonradiolabeled iothalamate clearance test using a validated procedure. Missing measured GFR assessments were imputed. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively.

   Time frame: Months 6, 12, 24, 36 and 84

5. Change in Calculated GFR at Months 12, 24, 36 and 84

   GFR was assessed using a true measure of glomerular filtration via nonradiolabeled iothalamate clearance test using a validated procedure. Missing measured GFR assessments were imputed. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively.

   Time frame: Baseline and Months 12, 24, 36 and 84

6. Number of Participants With Anti-Hypertensive Medications Used to Control Hypertension at 12, 24 and 36 Months

   Participants were determined to have hypertension at a particular time point if standardized systolic blood pressure ≥ 130 mm Hg or standardized diastolic blood pressure ≥ 80 mm Hg or participant had received an antihypertensive medication(s) for hypertension. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively.

   Time frame: Baseline and Months 12, 24 and 36

7. Percentage of Subjects Who Used Anti-Hypertensive Medications to Control Hypertension at Months 12, 24 and 36

   Participants were determined to have hypertension at a particular time point if standardized systolic blood pressure ≥ 130 mm Hg or standardized diastolic blood pressure ≥ 80 mm Hg or subject had received an anti-hypertensive medication(s) for hypertension. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively.

   Time frame: Months 12, 24 and 36

8. Percentage of Participants With New Onset Diabetes Mellitus (NODM) at 12, 24 and 36 Months.

   NODM was defined as participant who did not have diabetes prior to randomization. Participants were determined for NODM if the participant received an antidiabetic medication for a duration of at least 30 days, or at least two fasting plasma glucose (FPG) tests indicate that FPG is ≥ 126 mg/dL (7.0 mmol/L).

   Time frame: Months 12, 24 and 36

9. Systolic and Diastolic Blood Pressure (BP) at 12, 24 and 36 Months

   Participants were determined to have hypertension at a particular time point if standardized systolic blood pressure ≥ 130 mm Hg or standardized diastolic blood pressure ≥ 80 mm Hg or participant had received an anti-hypertensive medication(s) for hypertension. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively.

   Time frame: Months 12, 24 and 36

10. Mean Framingham Risk Score From Baseline to Months 12, 24 and 36

    The risk score was calculated based on the total points from six variables: Age, Level of LDL-cholesterol, Level of HDL-cholesterol, Presence and severity of systolic or diastolic hypertension, Presence or absence of a history of diabetes mellitus and Presence or absence of a history recent cigarette smoking. Total scores can range from \<-3 to \>14, which translate to a 1% to 56% risk of developing coronary heart disease in 10 years. Totals in the 4 to 6 point range translate to a 7 to 11% risk and 8 to 10 point range translate to a 18 to 27% risk.

    Time frame: Baseline and Months 12, 24 and 36

11. Percentage of Participants Using Lipid-Lowering Therapy at 12, 24, and 36 Months

    Dyslipidemia was defined as triglyceride ≥ 500 mg/dL \[5.65 mmol/L\], low density lipoprotein (LDL) ≥ 100 mg/dL \[2.59 mmol/L\], and non-elevated high density lipoprotein (HDL) ≥ 130 mg/dL \[3.36 mmol/L\]. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively.

    Time frame: Months 12, 24 and 36

12. Change in Total Cholesterol (TC), Non-HDL, LDL and HDL Cholesterol and Triglycerides at 12, 24 and 36

    Dyslipidemia was defined as triglyceride ≥ 500 mg/dL \[5.65 mmol/L\], low density lipoprotein (LDL) ≥ 100 mg/dL \[2.59 mmol/L\], and elevated non-high density lipoprotein (HDL) ≥ 130 mg/dL \[3.36 mmol/L\]. Here 'n' signifies those participants evaluable for this measure at specified time points for each arm, respectively.

    Time frame: Months 12, 24 and 36

13. Percentage of Participants Who Have an Acute Rejection by Months 6, 12, 24, 36 and 84

    Acute rejection was defined as central biopsy proven rejection that was either clinically suspected by protocol defined reasons or clinically suspected by other reasons and treated. Clinically suspected acute rejection was defined as an unexplained rise of serum creatinine ≥ 25% from baseline creatinine or an unexplained decreased urine output or fever and graft tenderness or serum creatinine that remains elevated within 14 days post--transplantation and clinical suspicion of acute rejection exists.

    Time frame: Months 6, 12, 24, 36 and 84

14. Number of Participants Using Lymphocyte Depleting Therapy and Steroid-Resistant for Acute Rejection by Months 6, 12, 24, and 36.

    Acute rejection was defined as central biopsy proven rejection that was either clinically suspected by protocol defined reasons or clinically suspected by other reasons and treated. Lymphocyte -depletion therapy for treatment of an episode of acute was defined as a participant treated with therapy and provided not treated with steroids earlier while steroid resistant acute rejection was defined as participants initially treated with steroids alone for suspected acute rejection for at least 2 days and then followed by the start of lymphocyte -depletion therapy.

    Time frame: Months 6, 12, 24 and 36

15. Number of Participants Based on Severity of Acute Rejection Based on Banff Grade Level by Months 6, 12, 24, 36 and 84

    Acute rejection was defined as central biopsy proven rejection that was either clinically suspected by protocol defined reasons or clinically suspected by other reasons and treated. Clinically suspected acute rejection was defined as an unexplained rise of serum creatinine ≥ 25% from baseline creatinine or an unexplained decreased urine output or fever and graft tenderness or serum creatinine that remains elevated within 14 days post--transplantation and clinical suspicion of acute rejection exists.

    Time frame: Months 6, 12, 24, 36 and 84

16. Mean Changes in Mental Component and Physical Component Health-Related Quality of Life (SF-36) From Baseline to Months 12, 24 and 36

    The SF-36 is a 36-item self-administered questionnaire developed to assess health-related quality of life (QOL) and comprises 8 domains, including 4 physical (physical health, bodily pain, physical functioning and physical role limitations) and 4 mental (mental health, vitality, social functioning, and emotional role limitation) subscales. Responses are used to derive physical and mental component summary scores, ranging from 0 to 100, with higher scores indicating better QOL (0=Poorest Health; 100=Best Health). Mean change from baseline = post-baseline value - baseline value; a higher value signifies improvement.

    Time frame: Baseline and Months 12, 24 and 36

17. Number of Participants With Clinically Significant Changes in Vital Signs up to 36 Months

    Participants with abnormal blood pressure, body weight and body temperature outside the defined normal range were graded as clinically significant vital signs by the investigator.

    Time frame: Day 1 to Month 36

18. Number of Participants With Laboratory Test Abnormalities up to 36 Months

    Participants with laboratory values outside the defined normal range were graded as clinically significant laboratory abnormalities by the investigator. Subjects were analyzed for Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase(AST), Hemoglobin, Platelet Count, Leukocytes, Bilirubin, Creatinine, Calcium, Bicarbonate, Potassium, Magnesium, Sodium, Phosphorus, Albumin, Uric Acid and Protein. Laboratory abnormalities were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3. Here 'n' signifies those subjects evaluable for this measure at specified time points for each arm, respectively.

    Time frame: Day 1 to Month 36

19. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Related AEs and SAEs, AEs Leading to Discontinuation and Who Died up to Month 36

    AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

    Time frame: Day 1 to Month 36

20. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Related AEs and SAEs, AEs Leading to Discontinuation and Who Died up to Month 84

    AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

    Time frame: Day 1 to Month 84

21. Percentage of Participants With Graft Loss or Death to Month 84

    Participant and graft survival at 84 months was summarized within each treatment group.

    Time frame: Randomization to date of death, up to 84 months

Baseline characteristics

Publications

• Dobbels F, Wong S, Min Y, Sam J, Kalsekar A. Beneficial effect of belatacept on health-related quality of life and perceived side effects: results from the BENEFIT and BENEFIT-EXT trials. Transplantation. 2014 Nov 15;98(9):960-8. doi: 10.1097/TP.0000000000000159. PubMed 24831918 ↗
• Pestana JO, Grinyo JM, Vanrenterghem Y, Becker T, Campistol JM, Florman S, Garcia VD, Kamar N, Lang P, Manfro RC, Massari P, Rial MD, Schnitzler MA, Vitko S, Duan T, Block A, Harler MB, Durrbach A. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant. 2012 Mar;12(3):630-9. doi: 10.1111/j.1600-6143.2011.03914.x. Epub 2012 Feb 2. PubMed 22300431 ↗

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