A Phase II Study of Belatacept (BMS-224818) With a Steroid-free Regimen in Subjects Undergoing Kidney Transplantation

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00455013
First received: March 30, 2007
Last updated: May 27, 2014
Last verified: May 2014
Results First Received: July 16, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Disorder Related to Renal Transplantation
Interventions: Drug: Thymoglobulin
Drug: Belatacept
Drug: Sirolimus
Drug: Tacrolimus
Drug: Mycophenolate Mofetil (MMF)

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
First 6 months (July 2007 to October 2008) assessed acute rejection of the renal transplant up to that time. All outcome measures were also assessed at 12 months post transplantation. Participants who wished to continue into the long term extension (LTE) signed a new consent form and were evaluated at 24, 36, and 48 Months post transplantation.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Epstein-Barr virus positive recipients of renal allograft from living or deceased donor. Excluded if panel reactive antibodies greater than, equal to (>=) 50 % or prior graft loss due to acute rejection. 93 participants randomized; 89 transplanted/treated: (1) fever on the day of surgery, (1) problem with allograft, and (2) withdrawal of consent.

Reporting Groups
  Description
Belatacept, Mycophenolate Mofetil (MMF) Thymoglobulin 1.5mg/kg for 4 days plus 4 corresponding doses of corticosteroids; intravenous infusion (IV) belatacept: 10 milligram per kilogram of weight (mg/kg) Day 1 (day of transplant) and Day 5, then every other week through Month 3 (Weeks 2,4,6,8,10,12), and then every 4 weeks through Month 6 (Weeks 16, 20, 24), after 6 months, 5 mg/kg every 4 weeks until 12 months; MMF (mycophenolate mofetil) 1g twice daily(BID). Participants were allowed to switch from MMF to sirolimus. Background immunosuppressive medications: methylprednisolone administered as 500, 250, 125, and 60 mg IV on Days 1, 2, 3, 4; thymoglobulin 1.5 mg/kg IV infusion on Days 1 (day of transplant), 2, 3, 4, up to maximum dose of 6 mg/kg.
Belatacept, Sirolimus Thymoglobulin 1.5mg/kg for 4 days plus 4 corresponding doses of corticosteroids; IV belatacept: 10 mg/kg Days 1 and 5, then every other week through Month 3 (Weeks 2, 4, 6, 8, 10, 12), and then every 4 weeks through Month 6 (Weeks 16, 20, 24),after 6 months, 5 mg/kg every 4 weeks until Month 12; sirolimus 5 mg/day on Day 1 and continued through Day 2, dosing to be adjusted to keep pre-dose C0 (concentration at time zero after administration) levels at 7-12 nanograms per milliliter (ng/mL) for first 6 months, followed by 5 - 10 ng/mL until 12 months. Participants were allowed to switch from sirolimus to MMF. Background immunosuppressive medications: methylprednisolone was administered as 500, 250, 125, and 60 mg IV on Days 1, 2, 3, 4, up to maximum dose of 6 mg/kg.
Tacrolimus, MMF Comparator regimen: thymoglobulin 1.5mg/kg for 4 days plus 4 corresponding doses of corticosteroids; oral tacrolimus 0.1 mg/kg/day in 2 divided doses with initial targeted trough level of 8-12 ng/mL for Days 1 - 30 with dose reduction to achieve 12 hour trough target of 5-10 ng/mL for 12 months; MMF 1g BID. Background immunosuppressive medications: methylprednisolone administered as 500, 250, 125, and 60 mg IV on Days 1, 2, 3, 4; thymoglobulin 1.5 mg/kg IV infusion on Days 1, 2, 3, 4 up to maximum dose of 6 mg/kg.

Participant Flow for 2 periods

Period 1:   Short Term Period
    Belatacept, Mycophenolate Mofetil (MMF)     Belatacept, Sirolimus     Tacrolimus, MMF  
STARTED     33 [1]   26 [2]   30 [3]
COMPLETED     27 [4]   21 [5]   28 [6]
NOT COMPLETED     6     5     2  
Adverse Event                 2                 5                 0  
Withdrawal by Subject                 0                 0                 1  
Lack of Efficacy                 4                 0                 0  
Unspecified                 0                 0                 1  
[1] 35 randomized, 33 transplanted and treated.
[2] 27 randomized, 26 transplanted and treated.
[3] 31 randomized, 30 transplanted and treated
[4] 5 discontinued belatacept by Month 6 (1 more by Month 12), 2 switched from MMF to sirolimus.
[5] 5 discontinued belatacept by Month 6; 10 additional switched from sirolimus to MMF.
[6] 1 discontinued tacrolimus by Month 6 and 2 discontinued by Month 12 (1 more by Month 12)

Period 2:   Long Term Extension (LTE)
    Belatacept, Mycophenolate Mofetil (MMF)     Belatacept, Sirolimus     Tacrolimus, MMF  
STARTED     27     19 [1]   27 [2]
COMPLETED     25     16     20  
NOT COMPLETED     2     3     7  
Adverse Event                 0                 1                 1  
Withdrawal by Subject                 1                 0                 1  
Death                 1                 1                 0  
No longer met criteria                 0                 0                 1  
Subject Request or refused                 0                 0                 3  
Poor non-compliance                 0                 1                 0  
non-specified                 0                 0                 1  
[1] 2 Participants chose not to enter the LTE.
[2] 1 Participant chose not to enter the LTE.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received transplant and were treated with drug were analyzed up to Month 12 post transplant.

Reporting Groups
  Description
Belatacept, Mycophenolate Mofetil (MMF) Thymoglobulin 1.5mg/kg for 4 days plus 4 corresponding doses of corticosteroids; IV belatacept: 10 mg/kg Days 1 and 5, then every other week through Month 3 (Weeks 2, 4, 6, 8, 10, 12), and then every 4 weeks through Month 6 (Weeks 16, 20, 24), after 6 months, 5 mg/kg every 4 weeks until Month 12; MMF 1g BID. Participants were allowed to switch from MMF to sirolimus.
Belatacept, Sirolimus Thymoglobulin 1.5mg/kg for 4 days plus 4 corresponding doses of corticosteroids; IV belatacept: 10 mg/kg Days 1 and 5, then every other week through Month 3 (Weeks 2, 4, 6, 8, 10, 12), and then every 4 weeks through Month 6 (Weeks 16, 20, 24),after 6 months, 5 mg/kg every 4 weeks until Month 12; sirolimus 5 mg/day on Day 1 and continued through Day 2, dosing to be adjusted to keep pre-dose C0 (concentration at time zero after administration) levels at 7-12 ng/mL for first 6 months, followed by 5 - 10 ng/mL until Month 12. Participants were allowed to switch from sirolimus to MMF.
Tacrolimus, MMF Comparator regimen: thymoglobulin 1.5mg/kg for 4 days plus 4 corresponding doses of corticosteroids; oral tacrolimus 0.1 mg/kg/day in 2 divided doses with initial targeted trough level of 8-12 ng/mL for Days 1 - 30 with dose reduction to achieve 12 hour trough target of 5-10 ng/mL for 12 months; MMF (mycophenolate mofetil) 1g BID.
Total Total of all reporting groups

Baseline Measures
    Belatacept, Mycophenolate Mofetil (MMF)     Belatacept, Sirolimus     Tacrolimus, MMF     Total  
Number of Participants  
[units: participants]
  33     26     30     89  
Age  
[units: participants]
       
<=18 years     0     0     0     0  
Between 18 and 65 years     33     24     26     83  
>=65 years     0     2     4     6  
Age  
[units: years]
Mean ± Standard Deviation
  49.2  ± 11.1     52.7  ± 10.8     53.6  ± 13.2     51.7  ± 11.8  
Gender  
[units: participants]
       
Female     8     6     8     22  
Male     25     20     22     67  
Region of Enrollment  
[units: participants]
       
North America     22     16     20     58  
Europe     11     10     10     31  



  Outcome Measures
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1.  Primary:   Number of Participants With Acute Rejection (AR) of Transplant up to 6 Months Post Transplantation - Intent to Treat (ITT) Population   [ Time Frame: Day 1 to Month 6 post-transplantation ]
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Measure Type Primary
Measure Title Number of Participants With Acute Rejection (AR) of Transplant up to 6 Months Post Transplantation - Intent to Treat (ITT) Population
Measure Description AR is clinicopathological event requiring clinical evidence and biopsy confirmation by central pathologist. One or more conditions were met and a renal biopsy revealed histologic evidence of rejection: unexplained rise of serum creatine (SCr) greater than or equal to 25% from baseline plus one or more of the following: unexplained decreased urine output; fever, graft tenderness; SCr that remained elevated 14 days post-transplantation and clinical suspicion of AR; other reason and participant treated for episode. Day 1=transplantation. Banff 97 working classification of kidney transplant pathology: Type I=tubulointerstitial AR without arteritis (IA: interstitial infiltration with >25% of parenchyma affected and moderate tubulitis with >4 mononuclear cells/tubular cross section; IB: >10 mononuclear cells; Type II vascular AR with (IA) intimal arteritis (IIA=mild - moderate; IIB=severe; Type III=severe rejection with transmural arterial changes, necrosis of smooth muscle cells.
Time Frame Day 1 to Month 6 post-transplantation  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants with more than one episode of AR were counted once only and the episode with the worst grade was used. For 95% Confidence Interval (CI) within each group, normal approximation was used if N greater than, or equal to (>=) 5. Otherwise, exact method was used. ITT population defined as all randomized and transplanted participants.

Reporting Groups
  Description
Belatacept, Mycophenolate Mofetil (MMF) Thymoglobulin 1.5mg/kg for 4 days plus 4 corresponding doses of corticosteroids; IV belatacept: 10 mg/kg Days 1 and 5, then every other week through Month 3 (Weeks 2, 4, 6, 8, 10, 12), and then every 4 weeks through Month 6 (Weeks 16, 20, 24), after 6 months, 5 mg/kg every 4 weeks until Month 12; MMF 1g BID. Participants were allowed to switch from MMF to sirolimus.
Belatacept, Sirolimus Thymoglobulin 1.5mg/kg for 4 days plus 4 corresponding doses of corticosteroids; IV belatacept: 10 mg/kg Days 1 and 5, then every other week through Month 3 (Weeks 2, 4, 6, 8, 10, 12), and then every 4 weeks through Month 6 (Weeks 16, 20, 24),after 6 months, 5 mg/kg every 4 weeks until Month 12; sirolimus 5 mg/day on Day 1 and continued through Day 2, dosing to be adjusted to keep pre-dose C0 (concentration at time zero after administration) levels at 7-12 ng/mL for first 6 months, followed by 5 - 10 ng/mL until Month 12. Participants were allowed to switch from sirolimus to MMF.
Tacrolimus, MMF Comparator regimen: thymoglobulin 1.5mg/kg for 4 days plus 4 corresponding doses of corticosteroids; oral tacrolimus 0.1 mg/kg/day in 2 divided doses with initial targeted trough level of 8-12 ng/mL for Days 1 - 30 with dose reduction to achieve 12 hour trough target of 5-10 ng/mL for 12 months; MMF (mycophenolate mofetil) 1g BID.

Measured Values
    Belatacept, Mycophenolate Mofetil (MMF)     Belatacept, Sirolimus     Tacrolimus, MMF  
Number of Participants Analyzed  
[units: participants]
  33     26     30  
Number of Participants With Acute Rejection (AR) of Transplant up to 6 Months Post Transplantation - Intent to Treat (ITT) Population  
[units: participants]
     
Total Number of Participants with AR     4     1     1  
Mild Acute IA     0     0     0  
Mild Acute IB     0     0     0  
Moderate Acute IIA     2     0     1  
Moderate Acute IIB     1     1     0  

No statistical analysis provided for Number of Participants With Acute Rejection (AR) of Transplant up to 6 Months Post Transplantation - Intent to Treat (ITT) Population



2.  Secondary:   Number of Participants With Acute Rejection of Transplant up to Month 12 Post Transplantation - Intent to Treat Population   [ Time Frame: Day 1 to Month 12 post transplantation ]

3.  Secondary:   Number of Participants With Graft Loss or Death up to Month 6 and Month 12 Post Transplantation - Intent to Treat Population   [ Time Frame: Day 1 to Month 6 and Month 12 post transplantation ]

4.  Secondary:   Number of Participants With Composite of Death, Graft Loss and Acute Rejection up to Month 6 - Intent to Treat Population   [ Time Frame: Day 1 up to Month 6 ]

5.  Secondary:   Number of Participants With Composite of Death, Graft Loss and Acute Rejection up to Month 12 - Intent to Treat Population   [ Time Frame: Day 1 up to Month 12 ]

6.  Secondary:   Number of Participants With Delayed Graft Function - Intent to Treat Population   [ Time Frame: From Day 1 up to and including Day 8 post transplantation ]

7.  Secondary:   Number of Participants With New Onset Diabetes Mellitus From Baseline to Month 12 Post Transplantation - Intent to Treat Population   [ Time Frame: Baseline to Month 12 ]

8.  Secondary:   Number of Participants Who Used Anti-hypertension Medications at Baseline and at 12 Months Post Transplantation - Intent to Treat Population   [ Time Frame: Baseline and Month 12 ]

9.  Secondary:   Mean Systolic, Diastolic and Arterial Blood Pressure at Baseline and Month 12 - Intent to Treat Population   [ Time Frame: Baseline and 12 months post transplantation ]

10.  Secondary:   Number of Participants Using Antihyperlipidemic Medications at Month 12 - Intent to Treat Population   [ Time Frame: Month 12 ]

11.  Secondary:   Mean Change From Baseline (BL) to Month 12 Post Transplantation in Lipid Values - Intent to Treat Population   [ Time Frame: Baseline to Month 12 ]

12.  Secondary:   Mean (Standard Deviation) in Calculated Glomerular Filtration Rate (GFR) mL/Min/1.73m^2 at Month 3, Month 6 and Month 12 Post Transplantation - Intent to Treat Population   [ Time Frame: Months 3, 6 and 12 post transplantation ]

13.  Secondary:   Number of Corticosteroid-free Participants at 6 and 12 Months Post Transplantation - Intent to Treat Population   [ Time Frame: Day 1 through Month 12 ]

14.  Secondary:   Number of Participants Who Were Corticosteroid-free at Months 6 and 12 and Number of Participants Who Were Both Calcineurin Inhibitor-free (CNI-free)and Corticosteroid-free at Months 6 and 12 Post Transplantation - Intent to Treat Population   [ Time Frame: Day 1 to Month 12 post transplantation ]

15.  Secondary:   Number of Participants With Acute Rejection of Transplant up to End of Month 48 Post Transplantation - Intent to Treat Population in Long Term Extension   [ Time Frame: End of Month 12 to end of Month 48 Post Transplantation ]

16.  Secondary:   Number of Participants With Graft Loss or Death at Months 24, 36, 48 Post Transplantation - Intent to Treat Population in Long Term Extension   [ Time Frame: End of Month 12 to end of Long Term Extension (Year 4) ]

17.  Secondary:   Mean (Standard Deviation) in Calculated Glomerular Filtration Rate (GFR) mL/Min/1.73m^2 at Months 24, 36 and 48 Post Transplantation - Intent to Treat Population in Long Term Extension   [ Time Frame: Months 24, 36 and 48 post transplantation ]

18.  Secondary:   Number of Corticosteroid-free Participants at Months 24, 36, 48 Post Transplantation - Intent to Treat Population in Long Term Extension   [ Time Frame: End of Month 12 to end of Long Term Extension (Year 4) ]

19.  Secondary:   Number of Participants Who Were Both Calcineurin Inhibitor-free (CNI-free)and Corticosteroid-free at Months 24, 36, 48 Post Transplantation - Intent to Treat Population in Long Term Extension   [ Time Frame: Months 24, 36, 48 ]

20.  Secondary:   Number of Participants Who Switched Between MMF and Sirolimus During Long Term Extension up to Study Completion   [ Time Frame: End of Month 12 to end of Study (Month 48) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Main limitations of this study include: small size (small number of participants in each treatment arm), the open-label nature of the trial, its exploratory nature, and the high rate of switches from sirolimus to MMF in one of the belatacept groups.


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