III. A Phase III Study of Belatacept-based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients (BENEFIT Study)
- Summarise the methodology and the conclusion of this study in your own words.
- What is the mechanism of action of this drug?
- What are the side effects of therapy?
- What are the precautions that should be taken before commencing such therapy?
It comparison belatatcept and cyclosporine
Co stimulation blocker bind with cd80 and cd 86 and inhibit action on on cd 28
Study compare between graft and patient survival at 1 year.
GFR at one year
Side effect
Abdominal or stomach pain.
agitation.
black, tarry stools.
bladder pain.
bloating or swelling of
the face, arms, hands, lower legs, or feet.
bloody or cloudy urine.
bone pain.
burning while urinating.
Portions of this document last updated: Sept. 01, 2021
Original article: https://www.mayoclinic.org/drugs-supplements/belatacept-intravenous-route/side-effects/drg-20074999
1-Summarise the methodology and the conclusion of this study in your own words.
1- comparing graft and patient survival at 1 year.
2- comparing GFR at 1 year.
3- comparing incidence and severity of acute rejection in the 1st year.
1- patient and graft survivals were similar in all groups.
2- GFR was even higher in patinets using Belatacept in both doses.
3- acute rejection was slightly higher in patients using Belatacept. it was 22% for MI Belatacept versus 17% for LI Belatacept versus 7% for Cyclosporine.
4- the safety was nearly similar in all groups. However, lymphoproliferative disorders were more in patients using Belatacept.
2- What is the mechanism of action of this drug?
3- What are the side effects of therapy?
4- What are the precautions that should be taken before commencing such therapy?
Phase III Study of Belatacept-based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients (BENEFIT Study)
This phase 111 trial over 3 years duration active controlled randomized trails from 100Diffeent centrs with the objective of this trial to determine the belatocept effcacy on both patient and graft survival as daul primary endpiont at month12,also to assess graft function by m GFR at 12 months or any reduction of mGFR by>10% in the ,M,LI,CNI group at 3 months ,12 months FU , and assess the Acute rejection rate among the three groups they included adults with age of 18 years and above from LD or standard cirteria DD , cold ischemia time < 24 hours, all patinets signed informed consents
Exclusion criteria;
1-Donor age above 60 or donor > 50s with two comorbid with creatinine of .1.5mg
2- cold ischemia time > 24 h
3- DCD donor si=ource
4-first transplant with initial PRA > 50% , or retransplant with PRA>30%
5- daul oragn transplant
randomization 1.1.1
initial maintenace IS were blinded for belatocepts groups but kept open for cyclsoprine group as theyneed to monitor the drug level
all have same induction with basiliximab D0,D4,,MMF 2gm , PMP 500mg then tapper off to < 2.5mg at day 15.
all patinets recieved antiviral , PJP prophylaxis first 3 months and another 3 mobthsin betatocept gruop
DSAs monitoring at baseline then 3,6,12 interval
this study conclude that belatocepts as primary maintenace IS was noniferior to cyclsporine based IS in term of effcacy and effect on both patient and graft survival in 12 months with better graft function asconfirmed by better mGFR compared to cyclsoprine group with less nonimmulogical metobolic effects but early acute rejection rate was higher in belatocepts groups after 12 months but did not affect the over all graft survival upon fU with better safety profile
1- What is the mechanism of action of this drug?
sepcific cositmulationCTLA4 blocker tragting the CD86/8 -CD28 and prevent Tcell activation
infusion related allergic reaction
anemia, lecupenia , gasteroentritis hypertension, infectons like UTI , CMV ,herpes viral infection PTLD more with belatoceptes
screen for EBV serollogy for recipients and should be avioded in EBV negative serollogy as its associated with higher rate of PTLD
aviod sun exposure and use UV light protection with sunscreen as its associated with skin cancers
Q1: BENEFIT is an acronym for Belatacept Evaluation of Nephroprotection and Efficacy as first-line Immunosuppression Trial. It was a phase III multicenter RCT with an active control group between 2006 to 2008 .The inclusion criteria was recipients 18 and older of a living or standard risk DD with cold ischemic time less than 24 hours. Exclusion criteria were recipients older than 60 or 50 with two risk factor, cold ischemia time over 24 hours and DCD or PRA positive .They were randomized to three groups:
1- More intensive dose of belatacept (MI)
2-Less intensive dose (LI)
3 – Cyclosporine maintenance group.
Primary outcome were evaluation at 12 -month including patient and graft survival, decrease renal function and acute rejection.
Secondary outcome were: mGFR, cGFR by MDRD formula and prevalence of CAN. Based on results they concluded that patients and graft survival had no difference between three groups.
Renal function at one year post-transplantation was similar too. But cardiovascular, metabolic adverse effects and chronic allograft nephropathy were seen lower in Belatacept comparing cyclosporine group. Rate of acute rejection during first year was higher in belatacept group but did not affect renal survival. So, belatacept is a safe immunosuppressant drug with less adverse effect comparing cyclosporine. Q2:
Belatacept selectively blocks CTLA-4 co-stimulation molecule by its fusion to FC fragment of IgG 1.
Q3:
Belatacept side effects including: 1 – infusion reactions 2 – urinary tract infections, nausea, constipation, edema and HTN 3- PTLD especially in pre-transplant EBV negative patients that restricts belatacept usage in EBV negative recipients. 4- Progressive multifocal leukoencephalopathy (PML).
Q4:
Precaution: Its usage in EBV negative, CMV positive patients is associated with PTLD. Check for these viruses. To avoid increasing rate of cancer use sunscreen with at least 15 (SPF) and protective clothes and avoid unnecessary sun exposure. Doing PPD test before its prescription is necessary to avoid tuberculosis reactivation. Bloody urine maybe a symptom for BK virus infection which could be increased by belatacept.
The benefit study , they studied belatacept efficacy and safety as a primary immunosuppression in comparison to cyclosporin .
Study conducted over 3 years , primary outcomes were obtained after all patients completed 12 month post transplant.
They study included 668 patients divided into 3 treatment groups , were randomized as 1:1:1 , receiving intense dose , low dose of belatacept and finally cyclosporin .
133 patients discontinued the study due to adverse effects and occurrence of rejections , and the the remaining 527 completed 12 month treatments post transplant.
The 1ry outcomes were to detect effect of each regimen on
*patient and graft survival .
* occurrence of renal impairment.
* incidence of acute rejection .
They concluded that belatacept treated patients was same as cyclosporin regarding patient and graft survival ,
Better regarding occurrence of renal impairment,
And inferior to cyclosporin regarding incidence of acute rejection
Mechanism of action of belatacept:
Is a selective costimulation blocker ,
It is a human fusion protein that combines modified EC portion of CTLA4 and the constant portion of the human IgG1 .
Side effects of belatacept:
Anaphylaxis
It increases risk of infections and cancers especially PTLD and skin cancers
Precautions of belatacept :
Should not be given to patients who are EBV ,IgG negative.
Should be given slowly IV over 30 min .
After belatacept patients should keep away from direct sunlight and use sun screens .
Patients should receive CMV prophylaxis
A Phase III Study of Belatacept-based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients (BENEFIT Study)
Summarise the methodology and the conclusion of this study in your own words.
BENEFIT is a 3-year, randomized, active-controlled, parallel-group, multicenter Phase III study conducted at 100 centers worldwide. The study includes patients 18 and older receiving a living donor or standard criteria deceased donor kidney transplant with an anticipated cold ischemia time of <24 h.
The sudy excluded recipients of extended criteria kidneys, prior or concurrent nonrenal solid organ transplants, first-time patients with a panel reactive antibody ≥50% and retransplants with a panel reactive antibody ≥30%.
Interventions
Patients were randomized 1:1:1,
· to receive a more intensive (MI) regimen of belatacept,
· a less intensive (LI) regimen of belatacept or
· cyclosporine for primary maintenance immunosuppression
The study was blinded to patients and study personnel with respect to belatacept dose regimen assignment but was open-label with respect to allocation to belatacept or cyclosporine.
Basiliximab induction (20 mg i.v. ) was given on the day of transplantation and D4 posttransplantation), mycophenolate mofetil (2 g/day p.o. in divided doses) and corticosteroids (initiated at 500 mg IV preoperatively and tapered to no less than 2.5 mg/day by Day 15.
Primary outcome of the BENEFIT study at 12 months
(1) composite patient and graft survival,
(2) composite renal impairment endpoint
(3) incidence of acute rejection
Secondary outcomes at Month 12
· mean measured glomerular filtration rate,(MDRD) equation
· prevalence of chronic allograft nephropathy on protocol biopsies at week 52
Cardiac and metabolic end points at week 12-
· Mean systolic and diastolic blood pressure
· incidence of new-onset diabetes after transplant (NODAT)
· mean changes in serum lipids.
Conclusion:
Belatacept shown:
· superior renal function
· similar patient/graft survival versus cyclosporine at 1 year post transplant
· Higher rate of early acute rejection
· higher incidence of PTLD in belatacept patients with known risk factors
· Overall safety was same as compared to cyclosporine
What is the mechanism of action of this drug?
selective T-cell (lymphocyte) costimulation blocker, binds to CD80 and CD86 on antigen-presenting cells thereby blocking CD28 mediated costimulation of T lymphocytes and thus inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-γ, interleukin-4, and TNF-α. Activated T lymphocytes are the predominant mediators of immunologic rejection.
What are the side effects of therapy?
· PTLD
· Non melanoma skin cancer
· PML
· Bacterial, Mycobacterial, Viral, and Fungal Infections.
· Mild infusion related reactions
· Proteinuria
· Immunogenicity
· NODAT
· Hypertension
· Gastrointestinal – nausea,diarhoea,vomiting
· Metabolic – hyperkalemia, hypokalemia,hypomagnesemia,hypophosphataemia
What are the precautions that should be taken before commencing such therapy?
· Epstein-Barr virus serology should be ascertained before starting administration of Belatacept, and only patients who are EBV seropositive should receive Belatacept.
· CMV prophylaxis is recommended for at least 3 months after transplantation.
· Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
· PML has been associated with high levels of overall immunosuppression- recommended doses and frequency of Belatacept and concomitant immunosuppressives, including MMF, should not be exceeded
· Patients should be evaluated for tuberculosis and tested for latent infection prior to initiating Belatacept. Treatment of latent tuberculosis infection should be initiated prior to Belatacept use.
· The use of live vaccines should be avoided during treatment with Belatacept
Summarise the methodology and the conclusion of this study in your own words.
BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) is a 3-year, randomized, active-controlled, parallel-group, multicenter Phase III study conducted at 100 centers worldwide.
– inclusion criteria:
age above 18 , 12 months post kidney transplantation , standerd risk criteria receiving living kidney donors or deceased of standerd criteria donors.
Anticipated cold ischemia time less than 24 hours .
-Exclusion criteria:
donors age 60, or 50 with at least two risk factors ( CVA, HTN, S Cr > 1.5 mg/dl), donation after cardiac death , and recipients of extended criteria , first transplant with cPRA >50% , or retransplant with cPRA >30%
prior or concurrent nonrenal solid organ transplants.
Patients are divided into a more intensive (MI) regimen of belatacept, a less intensive (LI) regimen of belatacept, or cyclosporine for primary maintenance immunosuppression.
All patients received induction with basiliximab followed by mentinance MMF and steroid.
The study was blinded to patients and study personnel with respect to belatacept dose regimen assignment and open-label with respect to allocation to belatacept or cyclosporine, due to the need for therapeutic dose monitoring in cyclosporine-treated patients.
Placebo infusions were utilized to maintain the blind between the belatacept dose regimens
The coprimary endpoints at 12 months were :
1 patient/graft survival,
2 composite renal impairment endpoint (percent with a measured glomerular filtration rate (mGFR) <60 mL/min/1.73 m2 at Month 12 or a decrease in mGFR 10 mL/min/1.73 m2 Month 3–Month 12)
3 incidence of acute rejection within 3 months,
Secondary outcomes:
mean measured glomerular filtration rate, mean calculated glomerular filtration
chronic allograft nephropathy .
Cardiovascular and metabolic endpoints at Month 12
included mean systolic and diastolic blood pressure, the incidence NODAT , and mean changes in serum lipids.
Conclusion
Belatacept groups was associated with similar to cyclosporine regarding patient and graft survival,
superior renal function.
less chronic allograft nephropathy
Better cardiovascular and metabolic profile compared with cyclosporine at 1 year
Both regimen of belatacept were similar no benefit of one over the other .
But there was increase in acute rejection in the early posttransplant period 3 month posttransplant it was not antibody-mediated, and generally resolve with treatment.
What are the side effects of therapy?
Treatment with belatacept-based regimens was generally safe-–there did not appear to be an increased incidence of serious adverse events, cytomegalovirus or BK polyoma virus infection or fungal infections through Month 12.
There was increase in incidence of
posttransplant lymphoproliferative disorder, particularly CNS in patients with known risk factors.
Other common side effects:
low levels of iron in the blood (anemia),(leukopenia), diarrhea,urinary tract infections ,electrolyte abnormalities,fever,back pain,joint pain
The most serious adverse reactions reported with Nulojix are infections specifically cryptococcal meningitis cytomegalovirus .
What are the precautions that should be taken before commencing such therapy?
not to be used in patients with negative EBV and with EBV positive donors due to increase risk of PTLD .
prophylaxis gainst CMV and Pneumocystis.
A Phase III Study of Belatacept-based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients (BENEFIT Study
Methodology:
BENEFIT; is a 3-year, randomized, active-controlled, parallel-group, multicenter Phase III study that includes 100 centers worldwide. The study begins in January 2006, and the primary endpoints were revised in June 2008 where all patients were at least 12 months post-transplant.
Patients:
Inclusion criteria:
· age 18 yrs and older.
· Receiving living donors or
· standard criteria deceased donor with cold ischemia < 24 hrs
exclusion criteria:
· Donors ≥ 60 years old
· Donor ≥ 50 years with at least two risk factors (cerebrovascular accident and sCr > 1.5 mg/dl)
· Cold ischemia time ≥ 24 hrs
· Donation after cardiac death
· Prior or concurrent non-renal solid organ transplants
· First-time patients with a PRA ≥ 50% or retransplants with a PRA ≥ 30%
patients provided signed informed consent
Intervention:
Patients were randomized 1:1:1, to receive a more intensive (MI) regime of belatacept, a less intensive (LI) regimen of belatacept or cyclosporine for primary maintenance immunosuppression. The study was blinded to the patients and study personnel for belatacept dose regimen and open-label with regard to allocation to belatacept or cyclosporine, because of the need for treatment dose monitoring in cyclosporine-treated patients. The induction was with basiliximab plus MMF plus steroid.
Outcomes
Primary outcomes include (1) composite patient and graft survival, (2) composite renal impairment endpoint and (3) incidence of acute rejection.
Secondary outcomes
Secondary outcomes at Month 12 included the mean measured glomerular
filtration rate, mean calculated glomerular filtration rate using the modification of diet in renal disease (MDRD) equation and the prevalence of chronic allograft nephropathy on protocol biopsies at Week 52, Cardiovascular and metabolic endpoints at Month 12 included mean systolic and diastolic blood pressure, the incidence of new-onset diabetes after transplant (NODAT), and mean changes in serum lipids. The intensity of antihypertensive therapy and dyslipidemia therapy was assessed at Month 12.
Statistical methods
All analyses were conducted on the intent-to-treat (ITT) population, which was defined as randomized patients who received a transplant.
Summary:
· In spite, of an increase in acute rejection in the early post-transplant period; Belatacept as compared with cyclosporine at 1 year posttransplantation, has:
1- similar patient and graft survival.
2- superior renal function
3- an improved cardiovascular and metabolic profile
4- less tendency toward chronic allograft nephropathy
It is safe and well-tolerated and has no renal toxicity as well, non-renal toxicities associated with calcineurin inhibitors.
· There is no additional efficacy obtained using the belatacept MI regimen compared with the LI regimen.
· The belatacept MI regimen gives no additional benefit to LI regimen.
· There is 13- 15 ml/min improvement in GFR among patients who received belatacept compared with cyclosporine. As well, better than that observed with sirolimus- or tacrolimus-based immunosuppression regime recipients. This improvement in GFR contributes to improvement in graft and patient survival.
The effect of belatacept on the renal function should be interpreted with other clinical profiles of belatacept as safety, cardiovascular and metabolic profile, and impact on acute rejection attack.
There were unexpectedly increased rates and grades of acute rejection in the belatacept-based regime compared with cyclosporine. Most of these episodes occurred within 3 months, were not antibody-mediated, and generally resolve with treatment. The rate in BENEFIT was similar to rates observed in other trials of calcineurin inhibitor-based regime in transplant recipients, with a range from 2% to 30%.
The study concludes that glomerular filtration rate and not acute rejection is a better predictor of long-term patient/graft survival.
Belatacept was associated with superior renal function and similar patient/graft survival as compared to cyclosporine at 1-year post-transplant, despite a higher rate of early acute rejection.
Summarise the methodology and the conclusion of this study in your own words.
Metholdology:
Multicentre study, 100 centres involved
Followup duration: 12 months posttransplantation
Patient selection : aging above 18 , undergoing kidney transplantation , of standerd risk criteria receiving from living kidney donors or deceased of standerd criteria donors
Anticipated cold ischemia time less than 24 hours
Exclusion criteria: donors aging 60, donors aging 50 with at least two risk factors ( CVA, HTN, s, cr > 1.5 mg/dl), donation after cardiac death , and recipients of extended criteria , first Tx with cPRA >50% , or retransplant with cPRA >30%
Patient were randomly divided into 3 equal groups 1:1:1, one received more intensive (MI) regimen of belatacept, one recieved less intensive (LI) regimen of belatacept, last one received cyclosporine for primary maintenance immunosuppression
All patients received induction therapy with : basiliximab induction (20 mg i.v. on the day of transplantation and 4 days posttransplantation), mycophenolate mofetil (2 g/day p.o. in divided doses) and corticosteroids (initiated at 500 mg IV preoperatively and tapered to no less than 2.5 mg/day by Day 15).
Fparameters of assessment through 12 mounths duration follow up period were: primary outcomes
(1) composite patient and graft survival, (1) composite renal impairment
(2) endpoint and (3) incidence of acute rejection
and assessment of DSA levels at baseline , 6 and 12 months
and Secondary outcomes at Month 12: eGFR using MDRD equasion, presence of chronic allograft nephropathy protocol biopsy at week 52, cardio (2). Cardiovascular and metabolic endpoints at Month 12 included mean systolic and diastolic BP, the incidence of new-onset diabetes after transplant (NODAT), and dyslipidemia.
Conclusion:
No superiority of Balatacept over CIs as regard graft and patient survival throughout the first year post Tx despite the fact that Baltacept arm was associated with higher incidence of graft rejection episodes
Belatacept showed improved cardiovascular/metabolic risk profile than CIs arm, belatacept was generally safe, although there was a higher incidence of PTLD
What is the mechanism of action of this drug?
Fusion protein acts as a selective costimulation blocker binding T-lymphocyte-associated antigen 4 (CTLA-4) with the (Fc) of human IgG1 (3), hence blocking the activation pathway of T cells and induction of allogenic immune response.
What are the side effects of therapy?
GIT:(diarrhea , constipation, nausea) , UTI,
Peripheral edema, mild acute infusion related side effects
Infection: Bacteria, viral , fungal, CMV, BK
PTLD
What are the precautions that should be taken before commencing such therapy?
Avoid use in patients with EBV negative serology as they will be highly prone to PTLD, selectivity using T-cell-depleting therapy and utilizing prophylaxis for cytomegalovirus infection.
Refrences:
(1) United Network for Organ Sharing National Data. Available at: http://www.unos.org/. 2008. Accessed November 15, 2009.
(2) Racusen LC, Solez K, Colvin RB et al. The Banff 97 working classif ication of renal allograft pathology. Kidney Int 1999; 55: 713–723.
(3) Larsen CP, Pearson TC, Adams AB et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005; 5: 443–453.
Summarise the methodology and the conclusion of this study in your own words.
. It is a randomized,3 -years, multicenter Phase III study. Inclusion criterias are patients 18 and older receiving a living donor or standard criteria deceased donor kidney transplant with an anticipated cold ischemia time of <24 h.
-Patients are divided into a more intensive (MI) regimen of belatacept, a less intensive (LI) regimen of belatacept, or cyclosporine for primary maintenance immunosuppression. All patients received MMF and steroid and induction with basiliximab.
-Belatacept was associated with similar patient and graft survival, superior renal function, a trend toward less chronic allograft nephropathy, and an improved cardiovascular and metabolic profile compared with cyclosporine 1-year posttransplant, despite an increase in acute rejection in the early posttransplant period. Belatacept was generally safe and well-tolerated. There appeared to be no additional efficacy gained using the belatacept MI regimen compared with the LI regimen. Belatacept is a new immunosuppressive therapy that avoids the renal and nonrenal toxicities associated with calcineurin inhibitors.
What is the mechanism of action of this drug?
–Belatacept, a selective costimulation blocker, is a human fusion protein combining a modified extracellular portion of cytotoxic T-lymphocyte-associated antigen 4 with the constant-region fragment of human IgG1.
What are the side effects of therapy?
Side effect
-Anemia, leukopenia.
-diarrhea-nausea ,constipation
-urinary tract infections
-electrolyte abnormalities
-fever, headache
-back pain, joint pain
-cold symptoms, sleep problems (insomnia).
-swelling in hands or feet.
-shortness of breath,wheezing,chest tightness,
-The most serious adverse reactions are infections specifically cryptococcal meningitis, cytomegalovirus, tuberculosis, and PTLD.
What are the precautions that should be taken before commencing such therapy?
-Belatacept should only be used in a patient who demonstrated EBV-seropositivity due to the risk of PTLD and PML.
1. Summarise the methodology and the conclusion of this study in your own
words.
BENEFIT Study:
Randomized, Control, multicenter Phase study.
Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression
Trial ,compare a more intensive (MI) or less intensive (LI) regimen of belatacept against
cyclosporine in adults receiving a kidney transplant .
primary objective:
1) patient and graft survival,
(2) Assess renal impairment endpoint .
(3) incidence of AR.
Secondary outcomes:
mean measured glomerular filtration rate, mean calculated glomerular filtration
chronic allograft nephropathy .
Cardiovascular and metabolic endpoints at Month 12
included mean systolic and diastolic blood pressure, the incidence of new-onset diabetes
after transplant (NODAT), and mean changes in serum lipids.
In BENEFIT, one of the largest studies in kidney allograft recipients, belatacept was
associated with similar patient and graft survival, superior renal function, a trend toward
less chronic allograft nephropathy and an improved cardiovascular and metabolic profile
compared with cyclosporine 1 year posttransplant, despite an increase in acute rejection
in the early posttransplant period.
2- What is the mechanism of action of this drug?
Belatacept, a selective costimulation blocker, is a human fusion protein combining a
modified extracellular portion of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
with the constant-region fragment (Fc) of human IgG1 .
2. What are the precautions that should be taken before commencing such
therapy?
Use only in patients who are EBV seropositive, Cytomegalovirus and pneumocystis
prophylaxis are recommended after transplantation.
3. What are the side effects of therapy?
1-PTLD.
2-Infection.
3-PML.
4-ANEMIA.
Summary of the BENEFIT Study:
Methodology:
A randomized controlled, parallel group, multicenter, Phase III study conducted over 3 years.
Aim: To assess effect of Belatacept on graft renal function and its long-term effects vs CNI on. patient and graft survival, acute rejection rates, malignancies and infections.
Out of 738 recruited patients, 686 were randomized in 3 groups, namely more intensive (MI), and low intensive (LI) Belatacept regimen and cyclosporine group. Additionally, all were given induction with basiliximab and were on MMF and steroids.
At 12 months post-transplant, the study showed that as compared to the cyclosporine group, the belatacept group had better GFR, decreased chronic allograft nephropathy similar patient and graft survival, increased PTLD, with increased rates and grades of acute rejection.
Conclusion: As compared to cyclosporine based regimen, Belatacept based immunosuppression regimen is safe and effective in kidney transplants with respect to patient and graft survival having a better graft function, cardiovascular and metabolic profile inspite of increased risk of acute rejections.
Mechanism of action:
Belatacept is a selective co-stimulation blocker; acting at signal 2 (interaction of CD80 and CD86 with the surface co-stimulatory receptor CD28 on T cell) of T cell activation, preventing T cell activation.
Side effects:
Anemia, diarrhea, nausea and vomiting as well as association with CNS lymphoma.
Precautions:
Infusion should be given through separate line and watch for infusion reactions. Avoid its use in patients with negative EBV serology and with EBV positive donors. CMV prophylaxis should be given.
Summarise the methodology and the conclusion of this study in your own word
This was a randomized, controlled, parallel group, multicenter conducted at 100 centers worldwide) , Phase III study done over 3 years.
Objective : To assess effect of Belatacept based regimen on graft and patient survival and rate of acute rejection versus CsA based regimen .
686 were randomized in 3 groups, more intensive (MI), and low intensive (LI) Belatacept regimen and cyclosporine group , all patient received induction with basiliximab and on MMF and steroids. Belatacept was found to have a similar patient and graft survival to cyclosporine and less chronic allograft nephropathy .Although belatacept had more acute rejection at 12 months, it was associated with a better renal function, cardiovascular and metabolic profile than cyclosporine. Both regimens of belatacept had similar effects.
What is the mechanism of action of this drug?
Belatacept is a recombinant and modified molecule (CTLA4–Ig) that interferes with the second activation signal of T lymphocytes, thereby causing a CD28–CD80/86 blockade.
What are the side effects of therapy?
Transplant lymphoproliferative disorder and progressive multifocal leukoencephalopathy are the most serious complications during belatacept therapy. Common side effects may include:
What are the precautions that should be taken before commencing such therapy?
The risk of developing PTLD is higher in patients who are EBV negative, have cytomegalovirus (CMV) infection so doctor must check CMV . Also may increase risk of certain types of cancer, especially of the skin Use sunscreen or sunblock lotions .Test for tuberculosis and avoid contact with any patient has infection .
1. This study is a phase III of randomized clinical trial (3-year, randomized, active-controlled, parallel-group, multicenter Phase III study conducted at 100 centers worldwide) that assesses the effect of MI or LI regimens of Belatacept versus cyclosporin in kidney transplant recipients from living or standard criteria deceased donors. Primary end points of this study were patient and graft survival, kidney dysfunction based on mGFR, and the incidence of acute rejection. Non inferiority or superiority depending on endpoints were identified.
Five hundred twenty-seven patients completed the initial 12 month treatment phase.
Both Belatacept regimens were associated with better patient and graft survival, superior kidney function, higher incidence of acute rejection episodes, a trend toward less chronic allograft nephropathy and an improved cardiovascular and metabolic profile compared with cyclosporine-based treatment.
An intriguing finding was the lower rate of acute rejection in the LI regimen compared to the MI regimen.
Of note, the mean measured glomerular filtration rate at Month 12 was higher in belatacept patients with acute rejection than in cyclosporine patients without acute rejection.
The 13-15 ml/min benefit in mGFR related to Belatacept therapy 1 year post transplant is significant and is associated with better long-term allograft and patient survival.
Early cellular rejections have minimal impact on long-term graft survival, and GFR at 1 year and not acute rejection correlates better with long-term graft survival.
In the case of Belatacept, episodes of acute rejection may be associated with lower tissue damage, so mGFR was significantly higher with Belatacept than cyclosporin. The reason proposed for this finding is the role of Belatacept in increasing the number of FOXP3+ Treg cells during acute rejection that imparts improved outcome of acute rejection.
Observed rates of donor-specific anti-HLA antibody production was lower in belatacept-treated patients versus cyclosporine.
Blood pressure and serum lipids were improved in the belatacept groups compared with cyclosporine. The incidence of NODAT was lower in Belatacept groups compared with the cyclosporin group.
2. CNIs may reduce long-term graft survival through chronic nephrotoxicity and resultant chronic allograft nephropathy. In addition, CNIs are associated with worsening hypertension, DM, and dyslipidemia that contributed to increased CV morbidity and mortality, the leading cause of death in 1 year post-transplant.
On the other hand, Belatacept is a selective costimulation blocker that combines CTLA4 with Fc region of human IgG1. Belatacept is designed to provide effective immunosuppression in the absence of renal and non-renal toxicities of CNIs.
3. Although safety issues were generally similar between two groups, posttransplant lymphoproliferative disorder, particularly CNS posttransplant lymphoproliferative disorder, was more common in the Belatacept groups (especially the MI regimen).
Most common adverse events were similar between groups. Acute infusion related adverse events (typically mild to moderate) were reported in the Belatacept group. UTI, the only serious adverse effect, occurred similarly between groups.
Overall, the frequency of bacterial, viral and fungal infections was similar among groups, as was the incidence of cytomegalovirus infection and BK virus infections. Tremor was reported more frequently in the cyclosporine group.
4. Posttransplant lymphoproliferative disorder cases occur in recipients with known risk factors, consisting of having Epstein-Barr virus (EBV) negative serology, pretransplant receiving T cell-depleting therapy as treatment for acute rejection and developing CMV disease. Therefore, utilization of Belatecept should be avoided in patients with EBV negative serology, T cell depleting agents should be used selectively, and prophylaxis for CMV infections should be considered.
1. Summarise the methodology and the conclusion of this study in your own words.
A Phase III Study of Belatacept-based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients (BENEFIT Study)
Methodology:
This was a randomized, active-controlled, parallel group, multicenter, Phase III study conducted over 3 years.
Aim: To assess effect of Belatacept on graft renal function and its long-term effects vis-a-vis CNI on the renal graft. The outcomes looked at included patient and graft survival, a composite renal endpoint (patients with measured GFR less than 60 ml/min at 12 months or fall in measured GFR from month 3 to month 12 by >10 ml/min), acute rejection rates, and complications including adverse effects, malignancies and infections.
Out of 738 recruited patients, 686 were randomized in 3 groups, namely more intensive (MI), and low intensive (LI) Belatacept regimen and cyclosporine group. Additionally, all were given induction with basiliximab and were on MMF and steroids.
At 12 months post-transplant, the study showed that as compared to the cyclosporine group, the belatacept group had better GFR, decreased chronic allograft nephropathy similar patient and graft survival, increased PTLD, with increased rates and grades of acute rejection. The belatacept group patients had better blood pressure and lipid control while increased adverse events were seen in cyclosporine group.
Conclusion: The authors concluded that, as compared to cyclosporine based regimen, Belatacept based immunosuppression regimen is safe and effective in kidney transplants with respect to patient and graft survival having a better graft function, cardiovascular and metabolic profile inspite of increased risk of acute rejections.
2. What is the mechanism of action of this drug?
Belatacept is a selective co-stimulation blocker (second-generation, derived from abatacept, having increased affinity to CD80 and CD86), acting at signal 2 (interaction of CD80 and CD86 with the surface co-stimulatory receptor CD28 on T cell) of T cell activation, hence preventing T cell activation. This promotes anergy and apoptosis.
3. What are the side effects of therapy?
There are no major side-effects of therapy: Anaemia, UTI, diarrhoea, constipation, nausea and peripheral oedema were a few side effects. Mild to moderate infusion reactions can be seen with belatacept. There is increased association with CNS lymphoma.
4. What are the precautions that should be taken before commencing such therapy?
As there is increased association with PTLD, avoid its use in patients with negative EBV serology and with EBV positive donors. T-cell depleting therapy should be judiciously used and CMV prophylaxis should be given. Infusion should be given through separate line and watch for infusion reactions.
Summarise the methodology and the conclusion of this study in your own words.
BENEFIT (Belatacept Evaluation of Nephro-protection and Efficacy as First line Immuno-suppression Trial) is a double blind RCT conducted on 686 patients who received either living or standard criteria deceased donor kidney transplant. Patients were divided according to the primary maintenance immune-suppression to 3 groups: more intensive regimen of belatacept , a less intensive regimen of belatacept or cyclosporine based. It was conducted in 100 centers around the world through 3 years. All patients had basiliximab induction, mycophenolate mofetil and corticosteroids.
Belatacept was found to have a similar patient and graft survival to cyclosporine and less chronic allograft nephropathy .Despite belatacept had more acute rejection at 12 months, it was associated with a better renal function, cardiovascular and metabolic profile than cyclosporine. Both regimens of belatacept had similar effects.
What is the mechanism of action of this drug?
It is costimulation blocker which selectively blocks T-cell activation . Belatacept is a human fusion protein combining a modified extracellular portion of (CTLA-4) with the (Fc) of human IgG1 .
What are the side effects of therapy?
· malignancies ,PTLD particularly CNS
· anemia, urinary tract infection, hypertension, constipation, diarrhea, nausea and peripheral edema
· acute infusional adverse events,
What are the precautions that should be taken before commencing such therapy?
· minimize PTLD risk : prophylaxis against CMV disease and minimizing T-cell-depleting therapy use in patients with EBV negative serology
· guard against infections: Make sure the patient have no current infection and cover with proper prophylaxis
· observe for infusion reaction
1.Summarise the methodology and the conclusion of this study in your own words.
Study Type:
Primary outcome:
Secondary outcome:
Study Objective:
Inclusion Criteria:
Exclusion Criteria:
Study Duration:
Study Population:
From 738 enrolled in the study only 686 were randomized in the three groups( more intensive and less intensive belatacept groups and CsA-group).Some patients in each group were discontinued from the study due to patient related issues or not meeting the criteria to continue on the phase trial.
Study Analysis:
2.What is the mechanism of action of this drug?
Belatacept is a human fusion protein and costimulation blocker that selectively blocks T-cell activation.
3.What are the side effects of therapy?
4.What are the precautions that should be taken before commencing such therapy?
a 3-year, 100-centre, randomized controlled, parallel-group Phase III research.
Belatacept intense, belatacept less intensive, or cyclosporine for primary maintenance immunosuppression were randomized 1:1:1. All patients got induction basiliximab and maintenance MMF with steroids.
At 12 months, each belatacept-based regimen will be compared to the cyclosporine-based regimen on three co-primary outcomes:
patient and transplant survival, renal impairment, and acute rejection.
Consequences:
Prevalence of chronic allograft nephropathy on protocol biopsies at Week 52 (Banff’97 categorization) -Mean changes in serum lipids and systolic and diastolic blood pressure were measured at Month 12.
Results
Belatacept and cyclosporine-based group graft survival
GFR was greater in the belatacept group than in the cyclosporine group.
Belatacept groups had greater acute rejection rates than cyclosporine groups.
The use of belatacept compared to cyclosporine increased the incidence of CNS PTLD.
What is the mechanism of action of this drug?
a costimulation blocker, that blocks T-cell activation, binds to CD 80/86 ligands of antigen-stimulating cells and inhibits the CD-28-mediated T-cell costimulation.
Side effects include an increased risk of cancer, and infection (CMV, opportunistic infection).diarrhea.
precautions: Avoidance in EBV positive/EPV negative
Summarise the methodology and the conclusion of this study in your own words.
Methods
BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial)
Study design ;
is a 3-year, randomized, active-controlled, parallel-group, multicenter Phase III study .
Study area ;
conducted at 100 centers worldwide (see Supporting Information, for complete list of study centers).
Approval ;
A data and safety monitoring board assessed cumulative safety and efficacy data on a regular basis throughout the trial, which remains ongoing.
Patients;
Inclusion criteria ;
patients 18 and older
receiving a living donor or standard criteria deceased donor kidney transplant with an anticipated cold ischemia time of <24 h.
exclusion criteria ;
Recipients of extended criteria kidneys .
donors ≥60 years old
donors ≥50 years old who had at least two other risk factors (cerebrovascular accident, hypertension and serum creatinine >1.5 mg/dL)
an anticipated cold ischemia time of ≥24 h
donation after cardiac death.
Additional exclusion criteria included prior or concurrent non renal solid organ transplants, and first-time patients with a panel reactive antibody ≥50% or retransplants with a panel reactive antibody ≥30%.
Interventional part ;
Patients were randomized 1:1:1, using an interactive voice response system and stratified by study site, to receive a more intensive (MI) regimen of belatacept, a less intensive (LI) regimen of belatacept or cyclosporine for primary maintenance immune suppression .
Outcomes ;
The primary objective of the BENEFIT study assessed each belatacept based regimen compared with the cyclosporine-based regimen on three co primary outcomes at 12 months:
(1) composite patient and graft survival.
(2) composite renal impairment endpoint .
(3) incidence of acute rejection.
Secondary outcome ;
Secondary outcomes at Month 12 included the ;
mean measured glomerular filtration rate.
mean calculated glomerular filtration rate using the modification of diet in renal disease (MDRD) equation (22,23).
prevalence of chronic allograft nephropathy on protocol biopsies at Week 52 .
Cardiovascular and metabolic endpoints at Month 12 included mean systolic and diastolic blood pressure.
incidence of new-onset diabetes after transplant (NODAT) .
mean changes in serum lipids.
Statistical method ;
Analyses were performed using a cumulative logit model with treatment groups as the covariate.
Conclusion of the study;
Results from BENEFIT suggest that this selectivity allows effective immune suppression, better preservation of renal function, an improved cardiovascular/metabolic risk profile and less toxicity compared with calcineurin inhibitors.
Treatment with belatacept was generally safe, although there was a higher incidence of PTLD in belatacept patients with known risk factors.
Outcomes will continue to be monitored over the duration of this 3-year study to help assess the overall profile of belatacept-based immune suppression.
What is the mechanism of action of this drug?
Belatacept is a first-in-class costimulation blocker that selectively blocks T-cell activation.
What are the side effects of therapy?
1-Infusional events were rare and mild or moderate in nature.
2-posttransplant lympho proliferative disorder, particularly CNS post transplant lympho proliferative disorder .
What are the precautions that should be taken before commencing such therapy?
The incidence of post transplant lympho proliferative disorder on belatacept may be reduced by minimizing use in patients with EBV negative serology, selectivity using T-cell-depleting therapy and utilizing prophylaxis for cytomegalovirus infection..
1-A multicenter randomize active controlled trial from Jan 2006to June 2008 including living donor or SCD with cold ischemia time less than 24 hours. Subjects were divided into 3 groups ;one with intensive regimen of belatacept,the other with less intensive regimen of belatacept and the control group with cyclosporine.In all patients ,induction with basiliximab was given &followed by MMF and steroids .
Conclusion:
graft survival was found comparable in both belatacept and cyclosporine groups. Higher GFR was found in both belatacept groups in comparison to cyclosporine group .On the other hand,high acute rejection rate was found in both belatacept groups compared to cyclosporine group. Belatacept use is generally safe,but it was associated with increased incidence of CNS PTLD compared to cyclosporine group..
2-Mechanism of action:
Belatacept is selective co-stimulation blocking agent through combination with CTLA-4resulting in inhibition of T-cells.
3-Side effects:
increased risk of malignancy, PTLD ,infection(CMV, opportunistic infection).Others include headache ,hypotension ,hypertension, constipation ,diarrhoea and LL edema.
4.Avoidance in EBV positive/EPV negative Tx .CMV prophylaxis .Avoidance or limitaTion use with T cell depleting agents and spacing by 12 hours far from ATG in case of concomitant use.
References:
Vincenti F. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374:2600–2601
(Nulojix (belatacept) [package insert]. Bristol-Myers Squibb. Belatacept (NULOJIX). Prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; revised April 2018
Methodology
it is a 3-year, randomized, active-controlled, double blind study conducted at 100 centers worldwide .Patient included were randomized , to receive a more intensive (MI) regimen of belatacept, a less intensive (LI) regimen of belatacept or cyclosporine for primary maintenance immunosuppression. They recieved induction therapy with basiliximab and maintenance with mycophenolate mofetil and corticosteroids for 12 month , then they continued on the maintenance doses till Month 36.
The primary outcomes upon which the groups were compared at 12 months are graft survival, renal impairment endpoint and the incidence of acute rejection.
The secondary outcomes at Month 12 were the mean measured glomerular filtration rate, mean calculated glomerular filtration rate using the(MDRD) equation , and the prevalence of chronic allograft nephropathy on renal biopsies at week 52, Cardiovascular and metabolic complications at Month 12 included mean systolic and diastolic blood pressure, the incidence of new-onset diabetes after transplant (NODAT), and mean changes in serum lipids.
Conclusion
Belatacept was associated with the same patient and graft survival, better renal function, a trend toward less chronic allograft nephropathy and an improved cardiovascular and metabolic profile compared with cyclosporine at 1 year posttransplant, in spite of increasing the acute rejection in the early posttransplant period.
2.What is the mechanism of action of this drug?
a costimulation blocker, that blocks T-cell activation ,It consists of a recombinant extracellular domain of human cytotoxic T lymphocyte antigen-4 (CTLA-4) and a fragment of a Fc portion of human IgG1. The drug binds to CD 80/86 ligands of antigen-stimulating cells and inhibits the CD-28-mediated T-cell costimulation. .
3.What are the side effects of therapy?
Anemia, urinary tract infection, hypertension, constipation, diarrhea, nausea and peripheral edema, , pyrexia, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia.
Serious adverse effects are post-transplant lymphoproliferative disorder specialy in patients that were not exposed to EBV before and progressive multifocal leukoencephalopathy and increases risk of cancer skin
4.What are the precautions that should be taken before commencing such therapy?
antiviral prophylaxis to all patients for at least 3 months posttransplant, and for 3 months upon initiating T-cell-depleting agents, as well as 6 months of prophylaxis against pneumocystis
it increases the PTLD risk in EBV seronegative patients and CMV infection if given with another T cell depleting drug
Reference
Melvin G et al. Belatacept: A worthy alternative to cyclosporine? J Pharmacol Pharmacother. 2012 Jan-Mar; 3(1): 90–92.
Randomized, active-controlled, parallel-group, multi center, phase III study.
Aim of study: assessment of efficacy of belatacept base IS regime ( in improving renal function, patient & graft outcome, & rejection rate after 12 months post transplant) comparing to cyclosporin based maintenance IS.
The enrolled recipient were from 100 center worldwide.
Inclusion criteria:
Exclusion criteria:
Randomization 1:1:1 ( high dose belatacept-, low dose belatacept-, cyclosporin-based maintenance IS). Induction with 2 doses of basiliximab & MMF+ tapering dose of steroid as maintenance. T-cell depleting agent used for patient on cyclosporin with anticipation of DGF or impaired renal function after renal transplantation.
Acute rejection grade <IIA treated with corticosteroids, >grade IIB treated with T cell depleted agent. Antiviral prophylaxis given for 3-6 months with 6 months prophylaxis for pneumocystis.
Primary outcome is to comparing belatacept to cyclosporin effects on :
Anti-HLA Ab assessed at 0,6,12 months & at time of any suspicion of acute rejection.
Secondary outcome:
Conclusion: Belatacept based maintenance IS regime was associated with similar graft & patients outcome, but better renal function & less CAN with improvement in CV & metabolic profiles when compared with cyclosporin.
Mechanism of action of belatacept:
It is selective T cell co-stimulation blocker. It bind to CD80/86 ligand found in APC, so it block CD28-mediated T cell co stimulation.
Most common side effects include anemia, diarrhea, UTI, peripheral edema, constipation, HT, pyrexia, cough, nausea & vomiting, headache, hypokalemia, hyperkalemia & leukopenia.
Precautions:
Methodology:
The study was randomized, active controlled, multi center study.
Inclusion criteria were age >18 years, living donor transplant or deceased donor kidney transplant with standard criteria and cold ischemia time <24 hours.
Exclusion criteria were extended criteria kidneys, donation after cardiac death, other solid organ transplant and PRA >50% in first transplant or >30% in retransplant
Interventions:
All patients were randomized into 3 groups, more intensive regimen of belatacept, less intensive and cyclosporine.
All patients received basiliximab induction, mycophenolate mofetil and steroids, they continued on maintenance therapy till month 36.
patients with AR <grade IIA were treated with steroids
T cell depleting therapy was given to patients in cyclosporine group expected to have DGF or impaired graft function and to all patients with acute rejection (AR) >Grade IIB.
All patients had protocol biopsies at time of transplant and at week 52.
Anti-donor HLA antibodies assessed at study baseline, 6 and 12 month post transplant and at any suspicion of rejection
Primary outcomes were prespecified, evaluated 12 months post transplant and included:
Secondary outcomes evaluated at month 12 included:
mean measured GFR and calculated GFR using MDRD
prevalence of chronic allograft nephropathy on protocol biopsies
mean systolic and diastolic blood pressure
new onset diabetes after transplant
delayed graft function
All were analyzed on the intent to treat population.
Conclusion:
Belatacept provides effective immunosuppression, better preservation of graft function, better metabolic profile and less non renal complications with avoidance of side effects of cyclosporine
graft and patient survival at 12 months post transplant were the same with belatacept and cyclosporine but belatacept was associated with higher rate AR early post transplant and more incidence of malignancy especially PTLD
Co-stimulation blockade therapy
biological drug that targets the CD28-CD80/CD86 pathway
It is a CTLA4-Ig construct that binds to CD80/CD86 and inhibit one of the costimulatory pathways leading to inhibition of activation of T cells (1)
Increased incidence of serious infections, most commonly UTI and CMV infections. (2)
Increased risk of PTLD especially CNS. (2)
Acute reaction is uncommon and is mild to moderate in nature (4)
No premedication is required before infusion. (3)
EBV serostatus as it carries a black box warning against use in EBV seronegative recipients. (4)
patient should have a good peripheral access because belatacept infusion will be monthly after the initial induction dose. (4)
history of hematological malignancy especially lymphoma and history of recent infection especially CMV should be considered. (4)
(1) van der Zwan M, Hesselink DA, van den Hoogen MW, Baan CC. Costimulation blockade in kidney transplant recipients. Drugs. 2020 Jan;80(1):33-46.
(2) Vincenti F. Belatacept and long-term outcomes in kidney transplantation. N Engl J Med. 2016;374:2600–2601
(3) Nulojix (belatacept) [package insert]. Bristol-Myers Squibb. Belatacept (NULOJIX). Prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; revised April 2018
(4) Perez CP, Patel N, Mardis CR, Meadows HB, Taber DJ, Pilch NA. Belatacept in solid organ transplant: review of current literature across transplant types. Transplantation. 2018 Sep 1;102(9):1440-52.
BENEFIT is a 3-year, randomized controlled, parallel-group, multicenter Phase III study conducted at 100 centers worldwide.
Inclusion criteria:
-Patients 18 and older receiving a living donor or standard criteria deceased donor kidney transplant with an anticipated cold ischemia time <24 h.
Exclusion criteria:
-Recipients of ECD
-prior or concurrent nonrenal solid organ transplants
-panel reactive antibody ≥50% or
-retransplants with a panel reactive antibody ≥30%.
Patients were randomized 1:1:1, to receive an intensive regimen of belatacept, a less intensive regimen of belatacept or cyclosporine for primary maintenance immunosuppression. All patients received basiliximab as induction and MMF plus steroids as maintenance therapy.
The primary aim is to assess each belatacept-based regimen compared with the cyclosporine-based regimen on three coprimary outcomes at 12 months:
(1) composite patient and graft survival,
(2) composite renal impairment endpoint and
(3) incidence of acute rejection.
Secondary outcomes:
-mGFR, eGFR using MDRD equation at Month 12
-Prevalence of chronic allograft nephropathy on protocol biopsies at Week 52 (Banff ’97 classification) -Cardiovascular and metabolic endpoints at Month 12 included mean systolic and diastolic blood pressure, the incidence of new-onset diabetes after transplant (NODAT), and mean changes in serum lipids.
Results
Similar Graft survival in both belatacept and cyclosporine-based group
GFR was higher in belatacept arm when compared to the conventional cyclosporine group
Acute rejection rate was higher in belatacept groups when compared to conventional cyclosporine group
Belatacept based regimen were associated with increased incidence of CNS PTLD when compared to conventional cyclosporine based group
Mechanism of action
Belatacept, a selective costimulation blocker, is a human fusion protein combining a modified extracellular portion of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with the constant-region fragment (Fc) of human IgG1.
Side effects
Among the most common (>25%) adverse events (anemia, urinary tract infection, hypertension, constipation, diarrhea, nausea and peripheral edema),
Summarise the methodology and the conclusion of this study in your own words.
In this study, 3 groups of adults receiving a kidney transplant from living or SCD are compared to each other in terms of the patient, graft survival, GFR, and incidence of acute rejection episodes at 1 year
All groups were using MMF, steroids, and basiliximab induction
Conclusion
What is the mechanism of action of this drug?
What are the side effects of the therapy?
What are the precautions that should be taken before commencing such therapy?
Summarise the methodology and the conclusion of this study in your own words
Methodology:
Setting: multicenter trial( conducted at 100 centers worldwide). from Jan 2006 to June 2008.
Design: randomized, active controlled, parallel group, phase III trial.
Patients: 18 years and older receiving either living donor or standard criteria donor with cold ischemia time of < 24hr. 736 patients were enrolled, 686 patients were randomized.
Exclusion criteria:
Ethical approval: by the institutional board review on each site.
The study was consistent with the ethical principles that have their origin in the current Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice.
Intervention:
Using interactive voice response,686 patients were randomized 1:1:1 for receiving a more intensive regimen of belatacept( 225), a less intensive regimen of belatacept( 230), or cyclosporine for maintenance therapy( 231).
each patient received basiliximab induction ( 20 mg on day 0 and day 4), MMF 2gm/day, and corticosteroids and after 12 months patients remained on maintenance therapy of the study through month 36.
Primary outcome:
compare belatacept based regimen to cyclosporine regimen for 3 outcomes at 12 months:
Secondary outcome:
Conclusion:
Belatacept was associated with:
What is the mechanism of action of this drug?
First class costimulation blocker that selectively blocks T cell activation.
What are the side effects of therapy?
What are the precautions that should be taken before commencing such therapy?
In patients with risk factors for PTLD:
Mechanism of action : it is co stimulation block agent block co-stimulatory pathway by blocking binding between CD28 on T cell and CD86,80 on APC, so prevent T cell activation.
Side effects :
1- anemia, urinary tract infection, hypertension, constipation, diarrhea, nausea and peripheral edema.
2- Acute infusion-related adverse events (within the first hour after belatacept infusion
3- malignancies (excluding nonmelanoma skin cancer): posttransplant lymphoproliferative
4- infections
The precautions that should be taken before commencing such therapy:
Not given in EBV negative patient to avoid development of PTLD
Prophylactic treatment of CMV should be given
Avoid or limit use of T cell depleting drugs
Methods and conclusions:
1- Design a 3-year, randomized, active-controlled, parallel-group, multicenter Phase III study conducted at 100 centers worldwide .
2- Patients included patients 18 and older receiving a living donor or standard criteria deceased donor kidney transplant with an anticipated cold ischemia <24 h>time of less than 24 hrs.
3- Interventions Patients were randomized 1:1:1, using an interactive voice response system and stratified by study site, to receive a more intensive (MI) regimen of belatacept, a less intensive (LI) regimen of belatacept or cyclosporine for primary maintenance immunosuppression. It is blinded to patients and study personnel.
4- Outcomes The primary objective of the study is to assess each belatacept based regimen compared with the cyclosporine-based regimen on three co primary outcomes at 12 months: (1) composite patient and graft survival, (2) composite renal impairment endpoint and (3) incidence of acute rejection.
5- Secondary outcomes Secondary outcomes at Month 12 included the mean measured glomerular filtration rate, mean calculated glomerular filtration rate using the modification of diet in renal disease (MDRD) equation (22,23), and the prevalence of chronic allograft nephropathy on protocol biopsies at Week 52. Cardiovascular and metabolic endpoints at Month 12 included mean systolic and diastolic blood pressure, the incidence of new-onset diabetes after transplant (NODAT), change in lipid profile.
6- Statistical methods All analyses were conducted on the intent-to-treat (ITT) population, which was defined as randomized patients who received a transplant.
Conclusion : treatment with balatecept is safe provided some precautions like not given in EBV negative patients , and give CMV prophylaxis and given with limitation of depleting antibody, it has favorable effects on graft outcome with less toxicity than cyclosporine group, as it improves metabolic/cardiovascular profile.
Summarise the methodology and the conclusion of this study in your own words.
Methodology-
BENEFIT is a 3-year, randomized, active-controlled, parallel-group, multicenter Phase III study conducted at 100 centers worldwide.
Inclusion criteria–
Patients 18 and older receiving a living donor or standard criteria deceased donor kidney transplant with an anticipated cold ischemia time of <24 h.
Exclusion criteria-
Recipients of extended criteria kidneys.
Prior or concurrent nonrenal solid organ transplants
first-time patients with a panel reactive antibody ≥50% .
retransplants with a panel reactive antibody ≥30%.
Interventions
Patients were randomized 1:1:1,
to receive a more intensive (MI) regimen of belatacept,
a less intensive (LI) regimen of belatacept or
cyclosporine for primary maintenance immunosuppression .
The study was blinded to patients and study personnel with respect to belatacept dose
regimen assignment .
it was open-label with respect to allocation to belatacept or cyclosporine.
Placebo infusions were utilized to maintain the blind between the belatacept dose regimens.
Each patient was treated with basiliximab induction (20 mg i.v. on the day of transplantation
and 4 days posttransplantation), mycophenolate mofetil (2 g/day p.o. in divided doses) and corticosteroids (initiated at 500 mg IV preoperatively and tapered to no less than 2.5 mg/day by Day 15.
Primary outcome of the BENEFIT study
Each belatacept based regimen compared with the cyclosporine-based regimen on three
co primary outcomes at 12 months:
(1) composite patient and graft survival,
(2) composite renal impairment endpoint
(3) incidence of acute rejection
Secondary outcomes-
Secondary outcomes at Month 12 –
the mean measured glomerular filtration rate,
mean calculated glomerular filtration rate using (MDRD) equation
prevalence of chronic allograft nephropathy on protocol biopsies at week 52.
Cardiac and metabolic end points at week 12-
Mean systolic and diastolic blood pressure
the incidence of new-onset diabetes after transplant (NODAT)
mean changes in serum lipids.
Conclusion –
Belatacept was associated with-
superior renal function
similar patient/graft survival versus cyclosporine at 1 year posttransplant
Higher rate of early acute rejection.
There was a higher incidence of PTLD in belatacept patients with known risk factors.
Overall safety was same as compared to cyclosporine.
What is the mechanism of action of this drug?
Belatacept, a selective T-cell (lymphocyte) costimulation blocker, binds to CD80 and CD86 on
antigen-presenting cells thereby blocking CD28 mediated costimulation of T lymphocytes and thus inhibits T lymphocyte proliferation and the production of the cytokines interleukin-2, interferon-γ, interleukin-4, and TNF-α. Activated T lymphocytes are the predominant mediators of immunologic rejection.
What are the side effects of therapy?
PTLD
Non melanoma skin cancer
PML
Bacterial, Mycobacterial, Viral, and Fungal Infections.
Mild infusion related reactions
Proteinuria
Immunogenicity
NODAT
Hypertension
Gastrointestinal – nausea,diarhoea,vomiting
Metabolic – hyperkalemia, hypokalemia,hypomagnesemia,hypophosphataemia
What are the precautions that should be taken before commencing such therapy?
1)Epstein-Barr virus serology should be ascertained before starting administration of Belatacept, and only patients who are EBV seropositive should receive Belatacept.
2)CMV prophylaxis is recommended for at least 3 months after transplantation.
3)Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
4)As PML has been associated with high levels of overall immunosuppression, the recommended doses and frequency of Belatacept and concomitant immunosuppressives, including MMF, should not be exceeded.
5)Patients should be evaluated for tuberculosis and tested for latent infection prior to initiating Belatacept. Treatment of latent tuberculosis infection should be initiated prior to Belatacept use.
6)The use of live vaccines should be avoided during treatment with Belatacept, including but not limited to the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.