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

Disorder Related to Renal Transplantation Clinical Trial

Official title:

A Randomized, Open-Label, Multicenter, Parallel-Group Study of Belatacept (BMS-224818)-Based Corticosteroid-Free Regimens in Renal Transplant

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00455013
• Other study ID #: IM103-034
• Status: Completed
• Phase: Phase 2
• First received: March 30, 2007
• Last updated: May 27, 2014
• Start date: July 2007
• Est. completion date: August 2012

Study information

• Verified date: May 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this clinical research study is to learn if belatacept (BMS-224818) is expected to show acceptable rates of acute rejection (AR) in steroid-free belatacept-based immunosuppressive regiments compared to a similar steroid-free tacrolimus regimen. The long-term safety and tolerability of belatacept based regimens following long-term administration in subjects who have received a kidney transplant

Recruitment information / eligibility

• Status: Completed
• Enrollment: 93
• Est. completion date: August 2012
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Living or deceased donor renal allograft

• Men and women, 18 to 70 years old

• Subjects who have received a de novo kidney transplant, who have completed the initial study treatment through Month 12, and are willing to sign informed consent will be eligible to continue into the long term extension phase

Exclusion Criteria:

• Pregnant or breastfeeding women

• Epstein Barr Virus (EBV) negative serology

• First time renal transplant with panel reactive antibody (PRA) = 50% or retransplantation with PRA > 30%

• Graft loss due to AR

• Positive T-cell or B-cell crossmatch

• Recipients/donors with HIV or hepatitis B/C

• Active tuberculosis (TB)

• Immunosuppressive therapy within 1 year of enrollment

• UNOS ECD organs will be excluded

• Body mass index (BMI) > 35 kg/m²

• Subjects who have developed any malignancy (other than non-melanoma skin cancer) or other medical condition that, in the investigator's opinion, should not be treated with an experimental immunosuppressive drug like belatacept

Related Conditions & MeSH terms

• Disorder Related to Renal Transplantation

Intervention

Drug:
• Thymoglobulin
Induction therapy, IV infusion, All subjects will receive thymoglobulin 1.5-mg/kg i.v. infusion on Days 1 (day of transplant), 2, 3, and 4 (up to a maximum total dose of 6 mg/kg) i.v. infusion over at least 4 hours
• Belatacept
Belatacept arms will receive i.v. belatacept (10 mg/kg) on Days 1 and 5, and then every other week through Month 3 (Weeks 2, 4, 6, 8, 10, and 12), and then every 4 weeks through Month 6 (Weeks 16, 20, and 24). After 6 months, subjects will receive belatacept at the maintenance dose of 5 mg/kg every 4 weeks until completion of the trial
• Sirolimus
Sirolimus will be initiated at 5 mg/day on Day 1 (day of transplant) and continued through Day 2. The dosing will be adjusted subsequently to keep pre-dose (C0) levels at 7 - 12 ng/mL for the first 6 months, followed by 5 - 10 ng/mL thereafter
• Tacrolimus
The recommended total initial dose of tacrolimus is 0.1 mg/kg/day in two divided doses orally up to and including week 52. Post week 52 subjects assigned to the tacrolimus arm will receive tacrolimus orally in accordance with local practice and the package insert until completion of the trial
• Mycophenolate Mofetil (MMF)
Administered orally in a capsule or solution formulation in 2 divided doses on a consistent schedule in relation to time of day and meals. The dose should be 1 g bid; however 1.5 g bid may be administered at the investigator's discretion until completion of the trial

Locations

Country	Name	City	State
Italy	Local Institution	Bologna
Italy	Local Institution	Brescia
Italy	Local Institution	Padova
Italy	Local Institution	Roma
Spain	Local Institution	Barcelona
Spain	Local Institution	Sevilla
United States	Albany Medical College	Albany	New York
United States	Medical College Of Georgia	Augusta	Georgia
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Northwestern University Feinberg School Of Medicine	Chicago	Illinois
United States	University Of Cincinnati	Cincinnati	Ohio
United States	Ohio State University Medical Center	Columbus	Ohio
United States	Denver Nephrology, Pc	Denver	Colorado
United States	University Of Colorado Health Sciences Center	Denver	Colorado
United States	Henry Ford Hospital	Detriot	Michigan
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Ucsf	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Acute Rejection (AR) of Transplant up to 6 Months Post Transplantation - Intent to Treat (ITT) Population	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.	Day 1 to Month 6 post-transplantation
Secondary	Number of Participants With Acute Rejection of Transplant up to Month 12 Post Transplantation - Intent to Treat Population	AR defined as a 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) >= 25 % from baseline plus one or more of the following: unexplained decreased urine output; fever and graft tenderness; a SCr that remained elevated within 14 days after transplantation and clinical suspicion of AR; reason other than those listed and participant was treated for this episode. Day 1 was day of transplantation. Banff grade used Banff 97 working classification of kidney transplant pathology. ITT population was all randomized and transplanted participants.	Day 1 to Month 12 post transplantation
Secondary	Number of Participants With Graft Loss or Death up to Month 6 and Month 12 Post Transplantation - Intent to Treat Population	Graft loss was defined as either functional loss or physical loss. Functional loss was defined as either: sustained level of SCr greater than or equal to (>=) 6.0 mg/dL (530 micromoles/Liter; micromol/L) for >= 4 weeks as determined by the local laboratory; regularly scheduled dialysis treatments over a period of 56 days; impairment of renal function to such a degree that the participant undergoes re-transplant. Day 1 was day of transplantation. ITT population defined as all participants randomized and transplanted.	Day 1 to Month 6 and Month 12 post transplantation
Secondary	Number of Participants With Composite of Death, Graft Loss and Acute Rejection up to Month 6 - Intent to Treat Population	Participants with graft loss or death prior to Month 6 were considered having an event of AR, therefore, the incidence of AR was reported as a composite of AR, death, and graft loss.	Day 1 up to Month 6
Secondary	Number of Participants With Composite of Death, Graft Loss and Acute Rejection up to Month 12 - Intent to Treat Population	Subjects with graft loss or death prior to Month 12 were considered having an event of AR, therefore, the incidence of AR was reported as a composite of AR, death, and graft loss.	Day 1 up to Month 12
Secondary	Number of Participants With Delayed Graft Function - Intent to Treat Population	Delayed graft function (DGF) is defined as participant requiring dialysis within the first week (Day 1-8) post transplantation. Participants losing their graft less than 48 hours post transplant and receiving chronic dialysis were not considered as having DGF. Day 1 was day of transplantation. Intent to treat population defined as all participants randomized and transplanted	From Day 1 up to and including Day 8 post transplantation
Secondary	Number of Participants With New Onset Diabetes Mellitus From Baseline to Month 12 Post Transplantation - Intent to Treat Population	Baseline defined as day before transplantation. A participant who did not have diabetes prior to randomization and received an antidiabetic medication for a duration of at least 30 days or a participant who meets the following criteria and did not have diabetes prior to randomization: Symptoms of diabetes plus casual plasma glucose (PG) concentration = 200 mg/dL (11.1 mmol/L); or fasting plasma glucose = 126 mg/dL (7.0 mmol/L); or 2-hour PG = 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test and a confirmatory laboratory test based on measurements of venous PG must have been done on another day in the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation.; Intent to treat population included all participants randomized and transplanted.	Baseline to Month 12
Secondary	Number of Participants Who Used Anti-hypertension Medications at Baseline and at 12 Months Post Transplantation - Intent to Treat Population	Baseline was defined as day prior to transplantation. Number of anti-hypertension medications taken were categorized from 1 to 6 and greater than (>)6. Intent to treat population included all participants randomized and transplanted.	Baseline and Month 12
Secondary	Mean Systolic, Diastolic and Arterial Blood Pressure at Baseline and Month 12 - Intent to Treat Population	Systolic, diastolic and mean arterial blood pressures were measured in millimeters of mercury (mm Hg). Baseline was defined as value obtained before transplantation. Intent to treat population included all participants randomized and transplanted.	Baseline and 12 months post transplantation
Secondary	Number of Participants Using Antihyperlipidemic Medications at Month 12 - Intent to Treat Population	Participants using > = 1 antihyperlipidemic medication at Month 12.	Month 12
Secondary	Mean Change From Baseline (BL) to Month 12 Post Transplantation in Lipid Values - Intent to Treat Population	Baseline (BL) was value obtained day prior to transplantation. Lipid values measured in milligrams/deciliter (mg/dL) included: high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), non-HDL cholesterol (non-HDL-C), total cholesterol (TC), triglycerides. Intent to treat population included all participants randomized and transplanted.	Baseline to Month 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	Blood urea nitrogen (BUN) in mg/dL; Albumin (Alb) in g/dL;Serum creatinine (SCr) in mg/dL; Age in years. Glomerular filtration rate (GFR) was calculated based upon serum creatinine (SCr) using the Modification of Diet in Renal Disease (MDRD) formula as suggested by Levey et al: MDRD GFR = 170 x [SCr/0.95]^(-0.999) x [Age]^(-0.176) x [0.762 if participant was female] x [1.180 if participant was black] x [BUN]^(-0.170) x [Alb]^(+0.318). Intent to Treat (ITT) population is defined as all participants randomized and transplanted.	Months 3, 6 and 12 post transplantation
Secondary	Number of Corticosteroid-free Participants at 6 and 12 Months Post Transplantation - Intent to Treat Population	Participants were said to be corticosteroid-free at Month 6 if they were not receiving corticosteroids for greater than (>) 7 consecutive days during Days 141 through Days 196, and at Month 12 if not receiving corticosteroids for > 7 days during Days 337 through 392. Intent to treat population included all randomized and transplanted participants.	Day 1 through Month 12
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	Participants were said to be CNI-free at Month 6 or 12 if they were not receiving a CNI during Day 141 to Day 196, or Day 337 to Day 392. Participants in the tacrolimus arm were not relevant to this analysis because tacrolimus is a calcinurin inhibitor. Participants were corticosteroid-free (CS-free) at Month 6 if they were not receiving corticosteroids for > 7 consecutive days during Days 141 through Days 196, and at Month 12 if not receiving corticosteroids for > 7 days during Days 337 through 392. Day 1 was day of transplantation. Intent to treat population included all randomized and transplanted participants.	Day 1 to Month 12 post transplantation
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	AR defined as a 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) >= 25 % from baseline plus one or more of the following: unexplained decreased urine output; fever and graft tenderness; a SCr that remained elevated within 14 days after transplantation and clinical suspicion of AR; reason other than those listed and participant was treated for this episode. Day 1 was day of transplantation. Banff grade used Banff 97 working classification of kidney transplant pathology. ITT population was all randomized and transplanted participants.	End of Month 12 to end of Month 48 Post Transplantation
Secondary	Number of Participants With Graft Loss or Death at Months 24, 36, 48 Post Transplantation - Intent to Treat Population in Long Term Extension	Graft loss was defined as either functional loss or physical loss. Functional loss was defined as either: sustained level of SCr greater than or equal to (>=) 6.0 mg/dL (530 micromoles/Liter; micromol/L) for >= 4 weeks as determined by the local laboratory; regularly scheduled dialysis treatments over a period of 56 days; impairment of renal function to such a degree that the participant undergoes re-transplant. Day 1 was day of transplantation. ITT population defined as all participants randomized and transplanted.	End of Month 12 to end of Long Term Extension (Year 4)
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	GFR was calculated based upon serum creatinine (SCr) using the Modification of Diet in Renal Disease (MDRD) formula as suggested by Levey et al: MDRD GFR = 170 x [SCr/0.95]^(-0.999) x [Age]^(-0.176) x [0.762 if participant was female] x [1.180 if participant was black] x [BUN]^(-0.170) x [Alb]^(+0.318). Age in years, Alb = Albumin in g/dL; SCr = in mg/dL; BUN =Blood urea nitrogen in mg/dL. Intent to Treat population is defined as all participants randomized and transplanted.	Months 24, 36 and 48 post transplantation
Secondary	Number of Corticosteroid-free Participants at Months 24, 36, 48 Post Transplantation - Intent to Treat Population in Long Term Extension	In the LTE, a participant was considered corticosteroid-free if they were not receiving corticosteroids for >7 consecutive days during Day 701 and Day 756, Day 1065 and Day 1120, as well as Day 1429 and Day 1484, respectively.	End of Month 12 to end of Long Term Extension (Year 4)
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	Participants were considered corticosteroid-free at Months 24, 36, and 48 if they were not receiving corticosteroids for >7 consecutive days during Day 701 and Day 756, Day 1065 and Day 1120, as well as Day 1429 and Day 1484, respectively. Participants were considered CNI-free at Months 24, 36, and 48 if they were not receiving CNI during Day 701 and Day 756, Day 1065 and Day 1120, as well as Day 1429 and Day 1484, respectively. Participants in the tacrolimus arm were not relevant to this analysis because tacrolimus is a calcinurin inhibitor.	Months 24, 36, 48
Secondary	Number of Participants Who Switched Between MMF and Sirolimus During Long Term Extension up to Study Completion	Long Term extension was the period from the end of Month 12 to the end of Month 48 post transplantation and the completion of the study 31 July 2012. At any time in the study, participants who were unable to tolerate MMF in the Bela-MMF and Tac-MMF groups could discontinue (DC) MMF and switch to sirolimus and remain in the study and those in the Bela-Siro group who were unable to tolerate sirolimus could DC sirolimus and switch to MMF and remain in the study. Study completion=data base (DB) lock.	End of Month 12 to end of Study (Month 48)

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm