Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin Induction in High Risk Renal Transplant Recipients

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1 Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin Induction in High Risk Renal Transplant Recipients Elisabeth Kincaide, PharmD PGY2 Solid Organ Transplant Pharmacy Resident University Health System Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center University of Texas Health San Antonio August 14 and 18, 2017 Learning Objectives: 1. Define acute rejection in renal transplant recipients 2. Describe induction therapy in renal transplantation 3. Summarize the current literature for rabbit anti-thymocyte globulin induction dosing strategies in high risk renal transplant recipients 4. Identify optimal rabbit anti-thymocyte globulin induction dosing in high risk renal transplant recipients

2 Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin Induction in High Risk Renal Transplant Recipients Elisabeth Kincaide, PharmD PGY2 Solid Organ Transplant Pharmacy Resident August 14 and 18, 2017 University Health System and McDermott Building Learning Objectives: At the completion of this activity, the participant will be able to: 1. Define acute rejection in renal transplant recipients 2. Describe induction therapy in renal transplantation 3. Summarize the current literature for rabbit anti-thymocyte globulin induction dosing strategies in high risk renal transplant recipients 4. Identify optimal rabbit anti-thymocyte globulin induction dosing in high risk renal transplant recipients Assessment Questions: 1. All of the following are risk factors for acute rejection in renal transplantation, except: a. Advanced recipient age b. Elevated panel reactive antibody c. Extended criteria donor d. Repeat renal transplant 2. Which agent is most efficacious for induction therapy in high-risk renal transplant recipients? a. Basiliximab b. Daclizumab c. Methylprednisolone d. Rabbit anti-thymocyte globulin 3. Optimal induction dosing for rabbit anti-thymocyte globulin in high risk KTR may include: a. 1.5 mg/kg x 1 day b. 1.5 mg/kg x 3 days c. 15 mg/kg x 5 days d. 1.5 mg/kg x 14 days ***To obtain CE credit for attending this program please sign in. Attendees will be ed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com ***Faculty (Speaker) Disclosure: Elisabeth Kinciade has indicated she has no relevant financial relationships to disclose relative to the content of her presentation KINCAIDE 2

3 Acute Rejection I. Acute rejection in renal transplantation 1,2 a. Cell mediated through alloreactive T-cells b. Typically occurs within 5 to 90 days after transplant, but can occur anytime II. Allorecognition 1,2 a. Prime event which initiates immune response b. Recognition of antigens displayed by the transplanted organ III. T-cell activation 1,2 a. APC activate T-cells through two signals i. Interaction between T-cell receptor and foreign antigens ii. Interaction between co-stimulatory receptors on the APC ligands and T-cells IV. Clonal expansion 1,2 a. Under the influence of cytokines, activation leads to clonal expansion b. Antibodies will flag graft cells for destruction c. Endothelial damage and graft ischemia occurs Figure 1: Steps in acute rejection V. Scientific Registry of Transplant recipients/organ Procurement and Transplantation (SRTR/OPTN) acute rejection rates in adult kidney transplant recipients 12 mo. post transplantation 3 Figure 2: SRTR/OPTN Acute Rejection Rates KINCAIDE 3

4 VI. Numerous risk factors for rejection have been identified 3-5 a. Risk factors are not equivalent b. Criteria to meet high risk is extremely center-specific Table 1: Factors increasing risk for rejection Young recipient age Increased donor age African American recipients Repeat transplant Elevated PRA Multiple HLA mismatches DSA Positive cross match Blood group incompatibility Risk for DGF, i.e. prolonged ischemic time, DCD, ECD, obesity, high donor creatinine Refer to Appendix A for abbreviations Maintenance Immunosuppression I. Maintenance therapy a. Purpose: prevent acute and chronic rejection b. Combination therapy is used to target different steps of the immune cascade while minimizing drug-related toxicity II. Most common triple immunosuppression at the time of transplant includes the following 3 a. Tacrolimus: 95% b. Mycophenolate: 93% c. Corticosteroid: 70% Induction Therapy in Renal Transplantation I. Induction therapy 1,4,5 a. Purpose: provide a high level of immunosuppression when the risk of rejection is the highest b. Essential in patients at high risk for rejection II. KDIGO guidelines recommendations 6 a. Interleukin-2 receptor antagonist as first line i. Basiliximab b. Suggest a lymphocyte-depleting agent for high risk KTR i. ratg KINCAIDE 4

5 III. Induction agents Nonlymphocyte depleting Lymphocyte depleting Daclizumab Basiliximab (Simulect ) Alemtuzumab (Campath ) Anti-thymocyte globulin (equine and rabbit) Figure 3: Immunosuppression therapy in KT IV. Immunosuppression a. Daclizumab and basiliximab are IL-2 receptor blockers i. Daclizumab was removed from the market in 2009 b. Campath is no longer commercially available and can only be obtained through the U.S. Campath Distribution Program c. Anti-thymocyte globulin i. Atgam equine formulation ii. Thymoglobulin rabbit formulation V. OPTN/SRTR annual data report induction agent use in adult KTRs 3 Figure 4: OPTN/SRTR induction agent use KINCAIDE 5

6 I. Description 7 a. Purified, pasteurized IgG obtained from immunizing rabbits with human thymocytes b. Serum is harvested and immunoglobulins are isolated c. Human red blood cells are used to deplete cross-reactive antibodies to non-t-cell antigens d. Exogenous viruses are removed II. Mechanism of action 7 a. Polyclonal antibody b. Lymphocyte depletion by complement-dependent cell lysis c. Cytotoxic antibodies directed against antigens expressed on human T-lymphocytes d. Targets: CD2, CD3, CD4, CD8, CD25, CD45 e. Ultimate effect: lymphocytopenia in blood and T-cell depletion in spleen and lymph nodes f. Rapid and dose dependent T-cell depletion g. T-cell recovery: one year 8,9 III. Adverse events and warnings 10 a. Anaphylaxis b. Central nervous system: chills, headache, fever, malaise, insomnia c. Cardiovascular: hypertension, peripheral edema, tachycardia, hypotension d. Respiratory: dyspnea, pulmonary disease e. Hematologic: leukopenia, thrombocytopenia, leukocytosis, anemia f. Immunosuppression: increased infection and malignancy risk i. Administer antibacterial, antifungal, and antiviral prophylaxis as clinically indicated g. Cytokine release syndrome i. Pre-medicate with corticosteroids, acetaminophen and/or antihistamine one hour prior to infusion IV. Monitoring 7,10 a. CBC with deferential and platelet count b. Vital signs during administration c. Lymphocyte count monitoring is recommended i. Total lymphocyte and/or T-cell subsets, e.g. CD3 monitoring V. ratg induction data in high risk KTR 15,16 Table 2: Trial summaries of ratg background literature Study Design N Intervention(s) MTN Result Safety Treatment failure of ratg 25% vs. Bas Infection in 38%, estimated ratg group 86% group difference of vs. 75%; p= % (95% CI: -24% leukopenia in 278 to -2%); p= ratg group 33% Brennan (2006) 15 Rabbit Anti-Thymocyte Globulin (Thymoglobulin ) Prospective, Randomized 1:1, open label, multicenter ratg 1.5 mg/kg POD0-4 (7.5 mg/kg cumulative) vs. Bas 20 mg POD0 and 4 CsA + MMF + steroids BPAR in ratg cohort Bas (26%) vs. ratg (16%); p=0.02 KINCAIDE 6 vs. 15%; p< subjects with lymphomas in ratg arm vs. 0

7 Table 2: Trial summaries of ratg background literature Study Design N Intervention(s) MTN Result Safety Noel Prospective, (2009) 16 randomized VI. 230 ratg 1.25 mg/kg POD0-7 (10 mg/kg cumulative) vs. Dac 1 mg/kg x 5 doses TAC + MMF+ steroids Treatment failure of ratg 25% vs. Dac 34%, estimated group difference - 8% (95% CI: -20% to 4%) BPAR in ratg cohort Dac (28%) vs. ratg (15%); p=0.016 See Appendix B for ratg efficacy data in KTR in both high and low risk populations infections/pt in ratg group 2.5 vs. 1.8; p=0.014 CMV 19% ratg vs. 11% Dac (p=0.093) PLT, WBC and lymphocyte count in ratg arm at 1 wk; p< subject in ratg arm developed metastatic melanoma VII. FDA indications and dosing in renal transplantation 7 Table 3: FDA-labeled indications of rabbit anti-thymocyte globulin Indication Approval Date Dose Treatment of acute rejection December mg/kg of body weight daily for 7 to 14 days Prophylaxis of acute rejection April mg/kg of body weight daily for 4 to 7 days Administer the first dosage over a minimum of 6 h and subsequent doses over a minimum of 4 h a. First dose given intraoperatively (Appendix C) 17 i. Blocking adhesion molecules that play a role in ischemia-reperfusion injury b. Dose modifications i. Reduce dose by one-half 1. WBC 2,000 to 3,000 cells/mm 3 2. Platelet count 50,000 to 75,000 cells/mm 3 ii. Consider stopping treatment 1. WBC count falls <2,000 cells/mm 3 2. Platelet count falls <50,000 cells/mm 3 KINCAIDE 7

8 VIII. ratg induction dosing debate a. Initial dosing of ratg was cumulative doses approximately 10.5 mg/kg 18 b. ratg dosing has been reported in numerous studies (Appendix C for trial summaries of ratg dosing in renal transplantation induction therapy) c. Transplant centers across the U.S. have not reached a consensus d. Cumulative dosing trends are declining 19 Figure 5: Total cumulative dosing of ratg reported by year with standard MTN regimen, adapted from Mohty et al. 19 Clinical Question What is the optimal dose of rabbit antithymocyte for induction therapy in high risk KTR? I. ratg induction in high immunological risk KTR 11,20,21 Table 4: Trial summaries of literature review Study Design N Intervention Gurk-Turner <7.5 mg/kg vs. >7.5 mg/kg (2008) 11 Retrospective 96 in high risk KTR Klem 4.5 mg/kg over three days vs. 6 mg/kg (2009) 20 Retrospective 93 over four days in high risk KTR 4.5 mg/kg over three days vs. Nafar (2017) 21 Prospective, open-label mg/kg over one day vs. 6 mg/kg over three days KINCAIDE 8

9 Literature Review I. Gurk-Turner (2008) 11 Table 5: Thymoglobulin dose optimization for induction therapy in high risk KTR 11 Objective Evaluate the total ratg dosing on graft outcomes in high immunological risk KTR Methods Design Retrospective cohort study Patient Inclusion Population Prior renal allograft transplantation OR PRA >40% Intervention Group I: ratg dose <7.5 mg/kg Group II: ratg dose >7.5 mg/kg 1.5 mg/kg was initiated intraoperatively and continued daily, target 7 10 doses Absolute CD3 lymphocytes were monitored daily, target <50 cells/mm 3 ratg doses increased if target CD3 were not achieved ratg doses reduced if WBC <2500 cells/mm 3 or platelets <75,000 cells/mm 3 Maintenance Tacrolimus when SCr <4 mg/dl or by POD4, trough goal 8 to 9 ng/ml and Infection Mycophenolate mofetil 1000 mg PO twice daily Prophylaxis Methylprednisolone IV POD0 2, tapered to oral prednisone (goal for African Americans 0.3 mg/kg and 0.15 mg/kg for all others) GCV 3000 PO mg/d or VGCV 900 PO mg/d, starting POD1 x 3 months TMP/SMX SS daily and clotrimazole 100 mg TID x 6 months Outcomes Graft and patient survival, incidence of AR, and 12-month SCr Graft loss defined as return to dialysis, retransplantation, or death with functioning graft Statistics Data presented as mean +/- SD or counts and percentages Students t-test, chi-square or Fisher s exact test Linear regression models to examine independent association between drug dosing and 1-year SCr Survival analysis methods to examine the independent association of ratg dosing and graft survival Schoenfeld test and log-minus-log survival plots were utilized for proportionality assumptions Stat/SE 9.2 software package (StataCorp, College Station, TX) Results Baseline N=96 (group I: N=33 and group II: N=63) Characteristics Retransplantation (85%), PRA>40% (19%) Approximately 45 years old, comparable donor source and HLA mismatch ratg dose (mg): 5.7 +/- 1.6 in Group I vs /- 2.1 in Group II; P<0.001 Group II had more African Americans (44.4% vs. 21.2%, P=0.03) 84.8% in Group I and 85.7% in Group 2 had daily CD3 counts <50 cells/mm 3 (P=0.44) Numerically higher females, % PRA, and delayed graft function in Group II Mean HLA class I mismatch 2.3 and DR mismatch 1.1 of total population (NS) KINCAIDE 9

10 Endpoints Author s Conclusion Outcome Graft survival (%) [study period] Patient mortality (%) [study period] Incidence of AR (%) [12 mo.] SCr (mg/dl) (± SD) [12 mo.] Biopsy-proven BKN (cases) CMV antigenemia (cases) Average WBC (x 10 3 cell/mm 3 ) Leukopenia (<2500 cells/mm 3 ) Thrombocytopenia (%) Average PLT count (cells/mm 3 ) Group I N=33 -Hematological AE reported [administration of ratg therapy] Group II N=63 P-Value 82.5% 79.4% (9) 4 (6.3) % 8.8% ± ± ± ± % 22% % 21.1% K 162K No independent association between ratg dose and graft survival found o ratg dose: hazard ratio 0.96, P=0.74, 95% CI: o Group II vs. Group I: hazard ratio: 0.85, P=0.79, 95% CI: Induction therapy in KTR, with previous renal transplant or elevated PRA percentage (>40%), with ratg doses equal to 7.5 mg/kg or less are as safe and effective compared to greater than 7.5 mg/kg doses in rates of AR and graft outcomes Investigators recommend no more than 5 doses of 1.5 mg/kg for ratg induction therapy in high risk KTR (7.5 mg/kg total cumulative dose) Reviewer s Critique Strengths Triple maintenance immunosuppression with TAC, MMF, and steroid 25.4 month mean follow up Limitations Retrospective review, selection bias, exclusion criteria not reported Results measured at different points in time Not reported why investigators chose a cutoff for CD3 <50 cells/mm 3 Dose adjustments based on protocol were not reported Whether or not cumulative ratg dose included treatment of acute rejection was not specified DSA not reported with baseline characteristics Data not well displayed or reported (BKN, retransplantation analysis, TMP/SMX and MMF discontinued) Small sample size, unpowered to detect relative hazard with statistical significance KINCAIDE 10

11 Take Home Points ratg dosing based upon daily CD3 levels, potentially showing that different doses may be optimal for different individuals, majority of the group required higher dosing >7.5 mg/kg Large selection bias, ratg >7.5 mg/kg were likely at a higher risk of rejection, therefore doses <7.5 mg/kg may have led to different efficacy outcomes Significantly higher BKN and thrombocytopenia in doses <7.5mg/kg may indicate that group had lower immune system with a quicker response to ratg II. Klem (2009) 20 Table 6: Reduced dose rabbit anti-thymocyte globulin induction for prevention of acute rejection in high risk KTR 20 Objective Compare ratg duration of three day vs. four day in high risk renal transplant recipients Methods Design Retrospective analysis Patient Inclusion: Major exclusion: Population Single organ renal transplant and one of Multi-organ transplant the following: o Retransplantation DGF requiring dialysis within the first 48 hours of transplant o African American race o PRA >20% Intervention Induction therapy with ratg o 1.5 mg/kg/day x three days o 1.5 mg/kg/day x four days First ratg dose was intraoperative Dosing based off postoperative course and suitability for discharge Maintenance TAC, trough goal 7 to 10 ng/ml until 3 mo. or CsA, trough goal 200 to 300 ng/dl and Infection Mycophenolate agent or SRL 2 mg daily, trough goal >5ng/dL Prophylaxis Methylprednisolone IV POD0 2, tapered to oral prednisone POD3, tapered to a goal of 5 mg daily by 6 mo. post-transplant VGCV 450 mg/d, x 3 mo to 6 mo (CMV D+/R-) TMP/SMX SS daily or pentamidine 300 mg monthly x 6 months Outcomes Biopsy-proven or treated acute rejection episodes Patient survival Graft survival Median hospitalization LOS for transplantation surgery egfr based on Modification of Diet in Renal Disease equation Infectious complications Statistics Chi-squared tests, Fisher s exact test, two-group t-tests, and Wilcoxon rank sum Results Baseline N=83 (three day ratg N=39; four day ratg N=44) Characteristics Approximately 48 years old, 61% Caucasian, 70% deceased donor, 18% African American Retransplantation (54%) overall; higher in four dose cohort 64% vs. 44%; p= % population with PRA >20%; 45% with PRA >80% Cold ischemia time >24 h greater in four dose cohort 12% vs. 0 KINCAIDE 11

12 Endpoints Mean SCr POD2 greater in the four-dose regimen 3.2% vs. 1.9%; P=0.005 Mean HLA mismatch 3.5 of the total population (NS) Three dose Four dose Regimen P-value N=39 N=44 TAC/MPA/Pred 74% 45% 0.01 TAC/SRL/Pred 26% 53% CsA/SRL/Pred 0 2% Clinical Endpoints Acute rejection, n (%) Total N=83 Three dose N=39 Four dose N=44 P-value 6 mo. 8 (10) 4 (10) 4 (10) mo. 9 (11) 4 (10) 5 (11) 1.00 Steroid responsive Humoral Graft and patient survival, (%) 6 mo mo Mean egfr, (SD; ml/min) 6 mo (16.3) 64.2 (16.2) 56.7 (15.7) mo (18.1) 63.4 (20.3) 54.6 (14.9) 0.03 Median egfr, (range; ml/min) 6 mo. 12 mo. BKV viremia, n (%) 57.9 ( ) 57.4 ( ) 62 ( ) 60.1 ( ) 56.7 ( ) 54.5 ( ) Total (%) 10 (12.1) 2 (5.1) 8 (18.2) mo mo Other infections, n (%) CMV 2 (2) 2 (2) Total bacterial 17 (20) 9 (23) 8 (18) 0.58 Neutropenia <1000 PMN/mL within 12 mo., n(%) 6 (7) 2 (5) 4 (9) 0.68 KINCAIDE 12

13 Transplant hospitalization length of stay (median days) 4 d (3 12) 3 (3 8) 4 (3 12) Author s Conclusion Supports the use of tailored ratg induction therapy in high risk KTR with immediate graft function Reviewer s Critique Strengths High risk factors better matched between groups for a retrospective study BKV surveillance protocol Attempt to control for confounders by excluding patients who received hemodialysis with 48 h post transplantation Limitations Retrospective, selection bias Donor information lacking Not all AR confirmed with biopsy Standard maintenance immunosuppression therapy was not used, greater SRL and CsA use in the four dose cohort Center was comparing efficacy of SRL vs. MPA during study period Take Home Points III. Nafar (2017) 21 Neutropenia assessed over 12 mo. Improvement of graft function on POD2 and suitability for discharge drove providers to stop ratg therapy in the three dose group Confounders within this study, including differences in maintenance regimens Due to retrospective nature and unmatched baseline characteristics, outcomes may have differed had the four dose group received three doses Table 7: The appropriate dose of thymoglobulin induction therapy in kidney transplantation 21 Objective Identify the most efficient and less toxic ratg dose in adult KTR Methods Design Randomized, prospective, open-label, single-center clinical trial Patient Inclusion: Exclusion: Population Positive PRA (>0%) Multiple organ transplants History of previous transplant Serological evidence of HIV years old Hepatitis B or C recipients or donors ECD Participation in another investigational study Cold ischemia time >6 h Intervention Arm A: 4.5 mg/kg IV over 3 days Arm B: 4.5 mg/kg IV x 1 day Arm C: 6 mg/kg IV over 3 days First ratg dose over 6 h beginning intra-operatively, subsequent over 4 h ratg doses halfed if WBC 2000 to 3000 cells/mm 3 or platelets 50 to 75,000 cells/mm 3 ratg doses held if WBC <2000 cells/mm 3 or platelets <50,000 cells/mm 3 Maintenance TAC (trough goal 7 to 10 ng/ml x 1 mo. and 5 to 7 ng/ml thereafter and Infection MMF 2 g pre-transplant, then 500 mg twice daily restarted on POD5 Prophylaxis TMP/SMX for PCP ppx; universal CMV ppx VGCV x at least 3 mo. Surgical prophylaxis and fluconazole for oropharyngeal candidiasis Outcomes Primary: rate and severity of acute rejection (biopsy-proven) 12 mo. post-transplant year KINCAIDE 13

14 Secondary: CMV infection, length of hospital stay, rate of readmission, incidence in hematological abnormalities, and renal function Statistics Sample size was determined on an alpha of 0.05 and a power of 0.80 with at least 30 patients per group Paired t-test for observations within each group, unpaired t-test for continuous variables, and Fisher s exact test for categorical variables All were two-tailed, a P-value of <0.05 was considered significant Intention-to-treat Results Baseline Characteristics Endpoints 100 screened, 10 excluded: kidney-pancreas transplant (N=2), positive HCV serology (N=1), participation in another study (N=4), cold ischemia time >6 h (N=3) N=90 adult KTR (N=30 patients per arm) Mean recipient age was 51 years old; mean donor age 34 years; 51% deceased donor; 30% previous transplant; mean PRA 12%; ECD 5%; mean cold ischemia time 41 minutes (NS) Protocol biopsies 12 mo. post-transplant achieved in 57% Efficacy Outcomes Arm A Arm B Arm C N=30 N=30 N=30 P-value SCr (mg/dl) (± SD) GFR (mg/ml) (± SD) Rejection types (n) Histologic evidence, n(%) Baseline 7.5 ± ± ± mo. 1.5 ± ± ± mo. 1.3 ± ± ± mo. 1.5 ± ± ± Baseline 9.3 ± ± ± mo ± ± 8 56 ± mo ± 6 66 ± ± mo ± ± 7 64 ± Cellular Humoral Glomerulitis 2 (7%) 1 (4%) 1 (4%) 0.03 Peritubular capillaritis 2 (7%) 0 1 (4%) Safety Outcomes Arm A N=30 Arm B N=30 Arm C N=30 P-value Infection (%) 7 (23%) 10 (33%) 9 (30%) 0.01 Viral KINCAIDE 14

15 Fungal Bacterial BKN, n(%) 2 (7) 2 (7) 7 (23) CMV infection (%) 5 (16%) 8 (26%) 10 (33%) Length of stay (days) 7.4+/ / / Readmission 11 (33%) 13 (42%) 12 (40%) WBC (cells/ml), 5 th d 4,800+/-500 5,100+/-300 4,000+/ PLT (cell/ml), 5 th 132,000+/- 108,000+/- 128,000+/- d Author s Conclusion Efficacy was similar amongst all three arms, but ratg 4.5 mg/kg over three days (1.5 mg/kg/day) regimen had significantly fewer complications Reviewer s Critique Strengths Randomized, prospective, no differences in baseline characteristics Recent (2014 to 2015) Triple immunosuppression Hematologic monitoring reporting around the time during ratg administration Acute rejection confirmed on biopsy Biopsy surveillance protocol First study looking at 4.5 mg/kg single dose in high risk KTR Limitations Only risk factor for is rejection retransplantation (~30% of the population) Patient population differs from U.S. Small sample size, effect size not reported ITT: 10% of Arm C received fewer than 3 doses; 16% in Arm B did not receive predetermined dose; groups inadequate to measure endpoints Statistics only reported between the groups Only 57% of enrolled patients had protocol biopsies at the end of the first year Take Home Points Not truly a high risk population, i.e. mean PRA 12%, ECD 5%, mean cold ischemia time 40 minutes, 30% retransplantation Overall, safety results favored the 4.5 mg/kg over 3 days cohort; BKN was significantly higher in the 6 mg/kg cohort Approximately half of the subjects did not receive their biopsies KINCAIDE 15

16 Conclusion and Recommendation I. Summary 11,20,21 Table 8: Literature review outcomes Gurk-Turner (2008) Klem (2009) Nafar (2017) Dosing strategy 1.5 mg/kg/d 1.5 mg/kg 1.5 mg/kg 1.5mg/kg 4.5mg/kg 2 mg/kg based on CD3 x 3 d x 4 d x 3 d x 1 d x 3 d Cumulative dose <7.5 mg/kg >7.5 mg/kg 4.5 mg/kg 6 mg/kg 4.5 mg/kg 4.5 mg/kg 6 mg/kg ACR/AMR 10% 9% 10% 11% 7% 7% 7% Graft survival 83% 79% % 100% Patient survival 91% 94% egfr (ml/min) BKN % 18.2% 7% 7% 23% CMV 2 3 2% 0 16% 26% 33% Infections % 18% 23% 33% 30% Note: Bolded items were found statically significant; Gurk-Turner ACR/AMR and patient/graft survival measured over duration >12 mo.; all other outcomes reported at 12 mo. II. Recommendation 11,20,21 a. High immunological risk i. African American, retransplantation, elevated PRA 10% to >80%, prolonged ischemia time, ECD b. ratg daily dose: 1.5 mg/kg i. 1.5 mg/kg day 1. Improved safety profile compared to alternative dosing strategies 2. Decreased LOS and readmission c. Duration of therapy: three vs. four day i. Recommend three day duration for patients with improved graft function, e.g. SCr <3 mg/dl d. Dosing range i. 4.5 mg/kg to 6 mg/kg given as 1.5 mg/kg daily dose III. Future ratg research in high risk KTR a. Prospective, randomized studies i. Adequately powered ii. Including adherence measurement for maintenance immunosuppression b. Intermittent dosing vs. two to three days in high immunological risk patients c. Three vs. four day duration d. Greater risk factors for inclusion criteria i. Development of standardized risk stratification calculator for dosing ratg e. Monitoring linked to efficacy outcomes i. Establish appropriate CD3 and/or absolute lymphocyte count (ALC) targets ii. Economic analysis of alternative dosing regimens 1. Measure outcomes on LOS, readmission, and laboratory costs KINCAIDE 16

17 Appendix A: Abbreviations AEs: adverse events APC: antigen presenting cells AR: acute rejection ATGAM : anti-thymocyte globulin equine Bas: basiliximab BCAR: biopsy-confirmed acute rejection BKN: BK nephropathy BKV: BK-virus BPAR: biopsy-proven acute rejection CMV: cytomegalovirus CNI: calcineurin inhibitor Dac: daclizumab DB: double-blind DCD: donation after cardiac death DD: double-dummy DD-rATG: divided-dose rabbit anti-thymocyte globulin DGF: delayed graft function DSA: donor specific antibody ECD: expanded criteria donor egfr: estimated glomerular filtration rate GCV: ganciclovir IL-2: interleukin-2 KDIGO: kidney disease improving global outcomes KT: kidney transplant KTR: kidney transplant recipients LOS: length of stay MC: multi-center MMF: mycophenolate mofetil Mo: months N: number NI: non-inferior PLT: platelet POD: post-operative day PRA: panel of reactive antibodies RCT: randomized control trial SC: single-center SCr: serum creatinine (mg/dl) SD-rATG: single-dose rabbit anti-thymocyte globulin SRL: sirolimus TAC: tacrolimus TMP/SMX: trimethoprim/sulfamethoxazole VGCV: valganciclovir Appendix B: Trial summaries of ratg induction efficacy data Study Design Intervention(s) Result Brennan Prospective, DB, (1999) 18 randomized ratg vs. ATGAM BPAR in ratg [Atgam (25%) vs. ratg (4%); p=0.009] Event-free survival was superior in ratg (94% vs. 63% p=0.0005) Hardinger (2004) 28 Randomized, DB (5-year) ratg vs. ATGAM Graft survival in ratg (92%) vs. Atgam (66%); p=0.007 Brennan (2006) 15 Prospective, randomized ratg vs. Bas BPAR in ratg cohort [Bas (26%) vs. ratg (16%); p=0.02] Noel (2009) 16 Prospective, randomized ratg vs. Dac BPAR in ratg cohort [Dac (28%) vs. ratg (15%); p=0.016] Martin (2011) 29 Retrospective, SC ratg vs. Bas BPAR less severe in ratg cohort [Bas (26%) vs. ratg (7%); p=0.02]

18 Appendix C. Additional review of ratg dosing in renal transplant recipients Study Design N Intervention(s) Result(s) Agha (2002) 22 Prospective, nonrandomized 88 Peddi (2002) 23 Prospective 41 Goggins Prospective, (2003) 17 randomized Wong Prospective, nonrandomized (2006) Tsapepas (2012) 24 Retrospective mg/kg followed by 1.5 mg/kg/d for a total of three days vs. 1.5 mg/kg/d for 7 days High risk kidney and kidneypancreas recipients dosed 1.5 mg/kg ratg when CD3+ counts rose >20 cells/mm 3 Intraoperative vs. postoperative doses of ratg induction therapy at 1 mg/kg/dose x 3 to 6 days 3-day induction at 1 mg/kg/d vs. 1.5 mg/kg/d Cumulative dose of 5 to 6 mg/kg vs. >6 mg/kg followed by steroid-sparring maintenance - AR (5 vs. 4%; p=1.0), graft survival (p=0.464) and patient survival (p=0.464) were similar - Lymphocyte depletion was more sustained and hospitalization significantly shorter in the three-day group - Mean total cumulative ratg dose was 4.5 mg/kg (average 3 doses per patients) - 4.9% patients died % acute rejection episodes - ratg intraoperative group was associated with significantly less DGF (14.% vs. 35.5%) and lower mean SCr on POD 10 and 14 (P<0.05) - AR rates were numerically lower 3.6% vs. 16%) in the intraoperative group - T-cell subsets (CD3+ and CD4+) were significantly lower at day 30, 90 and 180 and CD8+ lower at day 30 the 1.5 mg/kg group (p<0.05) - No episodes of acute rejection in either group - Significantly less BPAR in the >6 mg/kg cohort 11% vs. 21% (p<0.042) - Renal function and safety were similar Tenney (2015) 25 SC, retrospective vs. 5 doses of ratg - NS difference in BPAR, CMV or BK viremia Pennington (2015) 26 SC, retrospective 261 Stevens (2016) 27 Prospective, RCT, MC, DB, DD 95 <5mg/kg vs. >5 mg/kg cumulative dose based on ABW SD-rATG 6 mg/kg vs. DD-rATG 1.5 mg/kg/dose - No statistical difference in BCAR (p=0.944), CMV (p=0.385), BKV (p=0.55), or BKN (p=0.579) - SD-rATG was NI compared to DD-rATG (p=0.58) in the composite endpoint: fever, hypoxia, hypotension, cardiac complications, and DGF at 7 days - No difference in secondary end-points at 12-months: patient survival, graft survival, and rejection (p=0.78, p=0.47, p=0.35, respectively)

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