Rabbit-ATG or Basiliximab Induction for

Rapid Steroid Withdrawal after Renal Transplantation (Harmony):

an open-label, multicentre, randomised controlled trial

Oliver Thomusch, Michael Wiesener, Mirian Opgenoorth, Andreas Pascher, Rainer Peter Woitas, Oliver Witzke, Bernd Jaenigen, Markus Rentsch, Heiner Wolters, Thomas Rath, Tülay Cingöz, Urs Benck, Bernhard Banas, Christian Hugo†

University Hospital of Freiburg, Albert-Ludwigs University Freiburg, Freiburg, Germany

Chaken Maniyan M.D.

Nephrology Fellow, Phramongkutklao Hospital

25.11.2016

Nov 19, 2016 Volume 388 Number 10059

Introduction§Although KT is the best RRT, many recipients die prematurely with a functioning graft because of complications of immunosuppression

§From ELITE-Symphony study *, standard of immuno suppressive therapy consists of §Monoclonal IL-2 receptor (CD-25 Ag) Ab induction followed by

§Low-dose tacrolimus, MMF, and steroids

*Ekberg H, et al. Reduced exposure to calcineurin inhibitors in renal transplantation.N Engl J Med 2007; 357: 2562–75.

Introduction§ Low-dose tacrolimus arm compared with all other treatment arms à highest incidence rates of PTDM

§ Steroids can induce or worsen hypertension, hyperlipidaemia, and diabetes, which in turn can increase a transplant recipient’s CV events.

§Association between PTDM and CV events or mortality has been shown*

§Registry data as well as a case control study suggest that steroid-withdrawal protocols lead to a lower incidence of post-transplantation diabetes as well as superior long-term graft and patient survival**

*Vanrenterghem Y,. Transplantation 2000; 70: 1352–59.**Opelz G,.. Am J Transplant 2005; 5: 720–28

Introduction

Introduction§A randomised, multicentre study (Harmony) to assess which of two induction therapies was most efficacious at permitting rapid steroid withdrawal in tacrolimus-based and MMF-based immunosuppressive therapy within the first year

§ Efficacy of steroid withdrawal was assessed against the accepted gold standard immunosuppressive regimen (low tacrolimus plus MMF plus corticosteroid regimen, from the ELITE-Symphony trial).

Introduction§We tested whether induction therapy with rabbit antithymocyte globulin (ATG) was superior to induction therapy with basiliximab with respect to frequency of biopsy-proven acute rejection (BPAR) rate in the situation of rapid steroid withdrawal

§As secondary outcome parameters, we further tested hypotheses that rapid steroid withdrawal does not compromise patient or graft survival or graft function while improving a recipient’s cardiovascular risk profile, especially with respect to post-transplantation diabetes

Study design and participants

§The Harmony trial was prospective, randomised, open-label, multicentre study in three parallel study arms of adult renal transplant recipients.

§ Recruited from 21 centres in Germany.

Study design and participants

§ Per-protocol population was strictly defined to include only patients who received treatment according to protocol throughout the study period and reached the final follow-up after 12 months

§21 German centres enrolled 615 randomly assigned patients between Aug 7, 2008, and Nov 30, 2013

Inclusion criterion§Age 18-75 years , scheduled to receive a single-organ KT from either living or deceased donor

§Low immunological risk

§Donor and recipient had to be ABO compatible.

§Direct crossmatch had to be negative (complement dependent cytotoxicity crossmatch, CDC)

§Patients receiving a second KT were eligible (first allograft was not lost due to acute rejection within 1styear after KT.

Exclusion criterion

§ Grafts with pre-existing donor-specific HLA antibodies

§ PRA > 30%

§ Cold ischaemic time > 30 hr

§ Psychiatric disease;

§ Signs of alcohol or other drug abuse

§ Multiorgan transplantation;

§ History of cancer within last 5 years (except for non-melanoma skin cancer)

§ Signs of ongoing infections including HBsAg + HBcAb+ , anti-HIV+ , anti-HCV+

§ Bowel disease with malabsorption

§ Primary FSGS or MPGN

§Autoimmune disease which on steroid therapy

§ Thrombocytopenia < 70,000 , leucopenia <2500 neutropenia <1500

§Cirrhosis Child-Pugh B or C or serious liver disease

§Pregnantwomenandnursingmothers

Randomization and masking§ Centrally randomly assigned in 1:1:1 ratio.

§ Randomisation list was computer generated with SAS (ver. 8.1) and stratified according to individual centres.

§ Each participating centre received consecutively numbered, sealed envelopes.

§After receiving informed consent, the envelopes were opened to determine the type of immunosuppressive therapy.

§ Neither patients nor those giving treatment or assessing outcomes and analysing data were masked to the patients’ study group assignment.

Immunosuppression protocol§Arm A (control group)

§ Induction: basiliximab 20 mg IV on day 0 and 4§ Prolonged release tacrolimus OD at 0.2 MKD : § drug trough level 7–12 ng/mL within 1st month, § 6–10 ng/mL during months 2-3§ 3–8 ng/mL during months 4–12

§ MMF at two 1 g doses/day§ Prednisolone on day 0 and tapering with a requirement of dose of 10 mg /day

after 4 weeks § maintenance dose of 2.5–5.0 mg/day after 3 months

§In arm B, Same as in arm A with the exception that § Hereby, 500 mg prednisolone on day 0 were followed by

§ 100 mg on day 1,

§ 75 mg on day 2,

§ 50 mg on day 3,

§ 25 mg per day on days 4– 7

§ Corticosteroids were withdrawn from day 8

§In arm C, patients received same treatment as those in arm B, except § Induction with rabbit ATG instead of basiliximab.

§ Started intraoperatively, before graft reperfusion (1.5 MK Dose)

§ Rabbit ATG was given OD up to 4 days

§ Aiming for a total dose of 6.0 mg/kg bodyweight on postoperative day 3

§ The fourth dose of rabbit ATG on day 3 was omitted if the total count of lymphocytes was below 200/μL after third dose

Immunosupression protocol

Methods§All patients with either high-risk infection (recipient negative, donor positive) for CMV or EBV or patients who had induction therapy with rabbit ATG received at least a 3-month prophylaxis with valganciclovir.

§Additionally, Pneumocystis jirovecii pneumonia prophylaxis with trimethoprim and sulfamethoxazole or pentamidine was mandatory for all patients for at least 6 months.

Outcome§Primary efficacy endpoint à incidence of BPAR within the 1st year after KT

§ Compared BPAR incidence rates of study arm A with arm C and study arm B with arm C.

§All suspected episodes of acute rejection were confirmed by biopsy, with histological characteristics described according to the Banff criteria of 2005*

Banff ‘05 Meeting report: diff erential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (“CAN”). Am J Transplant 2007; 7: 518–26.

Secondary Outcome§Patient and graft survival

§Treatment failure

§Graft function (GFR Cockcroft Gault or CKD-EPI equation)

§Incidence of post-transplantation diabetes

§Systolic and diastolic blood pressure; lipids (HDL, LDL, and triglycerides); bodyweight

§ Incidence of CMV(PCR>1000 copies/μl), EBV (PCR>1000 copies/μl), or BK virus (PCR>10 000 copies/μl) infections;

§Incidence of malignancy;

§Wound healing disorders;

§Cataract formation; and osteoporosis.

Secondary Outcome§For post-transplantation diabetes assessment (according to the American Diabetes Association [ADA] recommendations), § fasting glucose concentration at each visit (0, 2, and 4 weeks, and 2, 3,

6, 9, and 12 months); § HbA 1cconcentration was measured at each visit except after 2

weeks§ OGTT was done at 3 and 12 months in all patients without a present

diagnosis of post-transplantation or pre-transplantation diabetes

§Treatment failure was defined any of § Use of additional immunosuppressive drugs, esp starting chronic

steroid drugs in arms B and C§ Discontinuation of any study drug > 21 consecutive days§ Allograft loss§ Death

Statistical analysis§Projected incidence primary endpoint BPAR (P A ) was estimated at 17% *

§Aim of our study was to show superiority of arm C versus arm A with respect to the BPAR rate (ie, a test of the null hypothesis: P C – P A = 0) and to show superiority of arm C versus arm B with respect to the BPAR rate (ie, a test of the null hypothesis: P C – P B = 0).

§The sample size was designed for both null hypotheses P C – P A = 0 and P C – P B = 0 to detect a difference in the BPAR rate between study arm A or B and study arm C with a statistical power of 80% and a split alpha value of 0·025.

§We calculated that 576 patients should be allocated to three study groups compensate for a dropout rate of 5%.

§All analyses were done on the basis of an intention-to-treat principle.

§Categorical data were compared with Fisher's exact test, and continuous variables with the Wilcoxon-Mann-Whitney test or t test.

§The time for reaching BPAR, graft loss, or death was calculated with the Kaplan-Meier method.

§Treatment comparisons were done with log-rank test.

§Incidences of adverse events and serious adverse events were tested by the Kruskal-Wallis Rank Sum Test.

*Ekberg H, et al. N Engl J Med 2007; 357: pp. 2562-2575** Asolati M, Harmon J, et al:. Am J Transplant 2004; 4: pp. 980-987

Results

Baseline characteristics

Cumulative probability of biopsy-proven rejection

Cumulative probability allograft survival

Outcome : primary endpoint

Outcome : secondary endpoint

Outcome : CV risk factor

Outcome : Post transplant infection

Cumulative probability of post-transplantation diabetes mellitus

Discussion§This study done in immunological low-risk patient to compare efficacy of two induction regimens, rabbit ATG versus basiliximab in combination with tacrolimus-based and MMF-based immunosuppressive regimen with or w/o rapid steroid withdrawal

§Although rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year

§ First multicentre, randomised study to show that rapid steroid withdrawal can be safely done w/o decrease efficacy with a tacrolimus and MMF-based regimen

Discussion§Rabbit ATG versus basiliximab was not superior in our study might be due to low immunological risk profile of recipients and relative low total dose of rabbit ATG

§The study is the first to show that rapid steroid withdrawal can be achieved without any negative effect on efficacy might be related to the low immunological risk profile of our mostly white study population

Discussion§Tacrolimus level were balanced in all groups at all timepoints except for one point shortly after corticosteroid withdrawal.

§Therefore, patients without rapid steroid withdrawal (arm A) had slightly lower tacrolimus trough level

§Tendency towards decreased daily MMF doses in rabbit ATG group compared with both basiliximabgroups à cannot exclude negative effect to BPAR

Discussion§Although efficacy was equivalent in all study arms, the second major finding of our study is that rapid corticosteroid withdrawal decreased the incidence of PTDM

§In trial used accepted criteria to define PTDM (ADA criteria of fasting glucose, OGTT, and HbA1c)

§ Rapid steroid withdrawal significantly decreases the incidence of PTDM > 40% (intention-to- treat), an effect is enhanced in per-protocol population

Discussion§Recent meta-analysis of steroid withdrawal between 3 and 6 months after KT did not show effect on PTDM incidence*, our early timepoint of steroid withdrawal might be crucial to this success

§ Frequency of PTDM diagnosis by ADA criteria was about twice as high as that of centre judgement in the Harmony study, and compared with most other trials (not incorporating all ADA criteria), suggests that §PTDM is overlooked, with all potential negative consequences for transplant patient

Pascual J,et al . Systematic review on steroid withdrawal between 3 and 6 mo after kidney transplantation. Transplantation 2010; 90: 343–49.

Discussion§ Incidence of adverse events was similar in 3 study arms.

§ Incidence of CMV, EBV infection was not statistically different§ valganciclovir was given to all in rabbit ATG arm, but only to high-risk in basiliximab arm.

§ Incidence of BK virus was not significantly different in all arms, but a numerical decrease > 40% was noted in steroid withdrawal basiliximab treatment arm

Discussion

§In our study, both rapid corticosteroid withdrawal groups were associated with a significantly higher incidence of anaemia and ESA use.

§This effect may attributable to corticosteroids effects

Limitation§ Premature study discontinuation of nearly 1/3 patients and unexpectedly low incidence of BPAR

§ Decreased incidence of PTDM was assessed only as predefined secondary endpoint.

§ Cannot completely exclude possibility of blinding bias ( decision about indication for biopsy involves subjective interpretation)

§ Follow-up period of 1 year is too short to§ Effect steroid-free maintenance therapy on BPAR§ Lasting effect on incidence of CV events or mortality§ (Harmony F/U period of 5 years, is being investigated

§ Limited to immunologically low-risk population of white ethnicity

Declaration of interests

§OT and CH received grant support, consulting fees, and lecture fees from Astellas, Sanofi, Genzyme, Roche Pharma, Novartis, and Wyeth/Pfizer. All other authors declare no competing interests.

Conclusion§Rabbit ATG did not reduce incidence of BPAR compared with

basiliximab with or without steroids

§ Both drugs equally successful in maintaining steroid-free

immunosuppression in > 80% of KT recipients, with benefits to PTDM

and without any loss of efficacy or safety signals besides

anaemia within the first year after KT

§ Rapid steroid withdrawal in a low-dose tacrolimus and MMF-based

regimen has potential new standard strategy for immunologically low-

risk population

§KDIGO suggest steroid withdrawn at evidence 2B§Tacrolimus SE : PTDM

§ELYTE SYMPHNY PTDM only 10 % Dx based on the notification of an adverse event,

Risk facotr for NODAT§Traditional risk factors — Many of the risk factors that predispose nontransplant patients to diabetes mellitus have been identified as risk factors for NODAT. These factors include:

§●Increased age (≥40 to 45 years) [10,12,19-27]

§●Obesity (body mass index of ≥30) [12,19,20,24,26-30]

§●African American race [12-14,22,26,31]

§●Hispanic ethnicity [12,27,31,32]

§●Family history of diabetes [22,33] or gestational diabetes

Transplant RF§Medication§ Steroid : risk of developing NODAT was 5 percent per

0.01 mg/kg per day increase in prednisolone dose.§CNI (Tac , cyclosporin) Tacrolimus is more diabetogenic

than cyclosporine§ Sirolimus§Aza and MMF NOT asso NODAT§ Statin , ACEI ARB and bactrim reduce NODAT§HCV infectin§HLA MM, HLA DR, HLAB27 phenotypre§POMg§ADPKD

Symphony trial § 12-month, prospective, randomized,open-label, multicenter study in four parallel groupsof adult renal-transplant recipients

§Primary end point

§–Estimated GFR 12 months after transplantation,(Cockcroft–Gault formula

§4 arm stadard CYC, lo CYC, lo tac, lo siro

§Result : GFR lo tac>lo CYC>stad CYC>sirolimus

§BPAR+ Rx failure : lo tac< stand CYC<lo CYC< siro

§DGF Siro BEST

§DM : low dose tac> siro> stadard>lo CYC

§A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction