3The “NIH Protocol” Improved RENAL not overall survival All classes of renal histology included100% CaucasianLong duration (11 months) of nephritis prior to entryExcluded patients with renal insufficiencyQuarterly cyclophosphamide therapy employedComorbidities over time not reported
4Racial Disparity: Renal Survival for Class IV Lupus Nephritis Treated with IV CTX % Probability of renal survivalp=0.007Years from renal biopsyM Dooley et al, Kidney Int 1997; 51:
5Renal Survival by Race at UNC Independent of the following factors:AgeDuration of SLEHistory of hypertensionHypertension control during therapyActivity or chronicity indices on renal biopsyPattern of corticosteroid therapy
6Diffuse GN (WHO IV) Austin, Sem Nephrol 19:2, 1999 Majority African American cohortsMajority caucasian cohortsAustin, Sem Nephrol 19:2, 1999
7Racial Disparity in response to cyclophosphamide Boumpas, Lancet 340:741, 1992
8Proportion without relapse Time (mo from starting IV CYC) Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamideRemissionProportion without relapseMedian time 79 mo20% relapse after 18 moTime (mo from starting IV CYC)RelapseMedian time 10 mo22% failed to remit after 2 yrProportion without remissionTime (mo from starting IV CYC)Time (mo from starting IV CYC)Median time 32 moRe-remissionProportion without re-remissionIoannidis JA et al. Kidney Int 2000; 57:
10Study endpoints MMF IVC Number randomized 71 69 Complete remission 16 4Partial remission2117No remission at 24 weeks on initial regimen19Crossover to alternate regimen612Withdrawal from study915
11Study withdrawals MMF IVC 6 early 13 early 3 late No deaths 2 late 5 severe disease1 non-compliance3 late2 crossover refusals1 toxicity (rash)No deathsIVC13 early3 treatment refusals (1 death)3 severe disease (2 deaths)6 non-compliance (2 with GI toxicity)1 lymphopenia2 late2 lost to follow-up
12University of Miami Study Methods: Study design & patient population Open label, randomized clinical trialInclusion criteriaAdults > 18 years of age, World Health Organization (WHO) classes III, IV, V with proliferationExclusion criteriaHave received IVCY > 7 doses or AZA > 8 weeksCreatinine clearance < 20 mL/minPregnancyAny clinically significant infection within 2 weeks of enrollment
13Cumulative probability Patient survival1.000.75Cumulative probability0.50p = 0.11, MMF vs IVCYp = 0.02, AZA vs IVCYp = 0.33, MMF vs AZA0.25AZAIVCYMMF0.00122436486072Time (months)
14Cumulative probability Free of relapse1.00p = 0.021, MMF vs IVCYp = 0.124, AZA vs IVCYp = 0.222, MMF vs AZA0.75Cumulative probability0.500.25AZAIVCYMMF0.00122436486072Time (months)
15MMF vs. CTX for Lupus Nephritis 350 Patient Two-Phase study with a6 month induction followed by up to3 year maintenance
16Euro-Lupus Nephritis Trial Renal functionAll patients (n = 85)High-dose IV CYC(n = 44)Low-doseIV CYC(n = 41)Normal673433Permanently impaired18108End-stage renal disease431Doubling of serum creatinine7Impaired renal function6Permanently impaired renal function was defined as a serum creatinine value that was repeatedly 1.4 mg/dl.Houssiau FA. Arthritis Rheum 50:
22Primary endpoint: responders in randomized population (n = 370) Assessed (n = 460)Excluded (n = 90)Randomized (n = 370)Open-label treatmentMMFIVCAllocated to MMF (n = 185)Received MMF (n = 184)Withdrawals (n = 35)Due to adverse event (n = 24)Consent withdrawn (n = 6)Other reason (n = 5)Allocated to IVC (n = 185)Received IVC (n = 180)Withdrawals (n = 29)Due to adverse event (n = 13)Consent withdrawn (n = 5)Other reason (n = 11)370 patients were randomized into the induction phase.83% completed the full 24 weeks, with most of the withdrawals being due to adverse events.Responders are eligible for re-randomization into the ongoing maintenance phase.FURTHER INFORMATIONInclusion criteriaAge 12–75 yearsDiagnosis of SLE per American College of Rheumatology (ACR) 1997 criteriaKidney biopsy within the 6 months prior to first randomizationLupus nephritis (International Society of Nephrology/Renal Pathology Society [ISN/RPS] 2003 classification) class III, IV-S, or IV-G, (A) or (A/C), or V, alone or in combination with class III or IVExclusion criteriaContinuous dialysis for more than 2 weeks before randomization and/or expected 8 weeksPancreatitis, gastrointestinal hemorrhage within 6 months, active peptic ulcer within 3 monthsSevere viral infectionSevere cardiovascular diseaseBone marrow insufficiency, with cytopenias not attributable to SLECurrent infection requiring intravenous antibioticsMaintenance phase:Double-blind, double-dummy, randomized (re-randomized), MMF orally 2 g/day or oral azathioprine 2 mg/kg/day with corticosteroids to a maximum of 10 mg/day, to treatment failure (or up to 3 years for last patient)Primary endpoint: responders in randomized population (n = 370)RespondersMaintenance phaseDouble-blind re-randomization to corticosteroids plus MMF or azathioprine for up to 3 years
23Demographic Characteristics: Intent-To-Treat Population MMF(n = 185)IVCTotal(n = 370)Male28 (15.1)29 (15.7)57 (15.4)Female157 (84.9)156 (84.3)313 (84.6)EthnicityHispanic64 (34.6)67 (36.2)131 (35.4)Non-Hispanic121 (65.4)118 (63.8)239 (64.6)RaceWhite75 (40.5)72 (38.9)147 (39.7)Asian62 (33.5)61 (33.0)123 (33.2)Other48 (25.9)52 (28.1)100 (27.0)Black26 (14.1)20 (10.8)46 (12.4)Non-black other22 (11.9)32 (17.3)54 (14.6)The groups were well balanced with regard to sex, ethnicity and race.The racial/ethnic breakdown reflects where the study was performed.All patients were reported as either Hispanic or non-Hispanic.The majority of Hispanic patients were mixed-race, but some were black or CaucasianFURTHER INFORMATIONThe groups were generally balanced. Consistent with the demographic profile of patients with LN, the race/ethnicity breakdown simply reflects where the study was performed.Race/ethnicity were self-reported. ‘Other’ comprises predominantly mixed race from Latin America, known locally as mestizo. Note that in the efficacy analysis, ‘Other’ also includes Black patients.
24Baseline Disease Characteristics by Race (ITT Population) CaucasianBlackAsianOtherMMFIVC(n=75)(n=72)(n=26)(n=20)(n=62)(n=61)(n=22)(n=32)DurationSLE6.3(5.9)7.2(6.9)5.7(8.2)5.0(4.1)3.6(4.2)2.3(2.5)8.5(7.2)5.9(6.8)Duration LN3.0(3.9)4.3(6.0)1.8(2.1)2.8(3.3)(3.6)1.9 (2.2)3.5(4.7)(4.4)Urine Protein: Cr ratio3.7(3.2)3.8(2.9)4.7(5.6)4.1(2.8)(3.8)Estimated GFR83.1 (44.8)81.7 (38.1)103.8 (44.5)97.1 (56.0)86.4 (42.6)103.4 (47.7)66.0 (34.9)91.9 (43.1)When looked at by race, it is most notable that patients assigned to MMF in the Asian and Other racial groups appear to have worse renal function both with respect to the mean/median GFR than those in the IVC group.Also of importance (but not on this slide) is that there were more patients with very low GFR (<30) assigned to MMF than IVC. This is important when we see look at the safety data.
25Drug Exposure by Race Caucasian (n = 72) Black (n = 20) Asian (n = 61) Other(n = 32)MMF mean daily dose71266121Mean (SD)2.45 (0.46)2.49 (0.45)2.40 (0.77)2.74 (0.45)Min, Max1.0, 3.31.5, 3.20.3, 6.81.8, 3.6Number of IVC infusions1860315.8 (0.8)4.8 (1.6)5.6 (1.2)5.7 (1.1)1.0, 6.02.0, 7.0Around 70% patients finished the study on 2.5–3.0g MMF, indicating the drug was well tolerated in this population.The Asian patients appeared to tolerate the same mean daily dose MMF as the other groups.FURTHER INFORMATIONTarget dose was achieved for the majority of patients in both groupsThe majority of patients in both groups complied with the corticosteroid taper – therefore not a confounding factorThe duration and mean number of infusions were less in black patients than in the other groups, possibly due to tolerability issues.
26Treatment Compliance Oral MMF twice daily Mean (SD): 2.5 (0.58) (g/day)Oral corticosteroids twice dailyIVC in monthly pulsesMean dose per infusion:0.78 g/m2Mean (SD) doses per month: 5.6 (1.1)Target dose was achieved for the majority of patients in both groups.The majority of patients in both groups complied with the corticosteroid taper.
27Primary Endpoint: Responders at Month 6 Response was judged by a blinded Clinical Endpoint Committee, by the criteria:Decrease in urine protein/creatinine ratio (P/CR)– to <3 in patients nephrotic at baseline (P/CR ≥3),– or by ≥50% in patients subnephrotic at baseline (P/CR <3)andStabilization of serum creatinine level (24-week level ±25% of baseline), or improvementResponse comprised of a hard, reproducible laboratory endpoint, measured at a central laboratory from 24-hour urine collections.In addition, a blinded committee adjudicated the response.NB: nephrotic patients had to become sub-nephrotic and sub-nephrotic patients had to reduce their P/CR by at least 50%.Proteinuria is defined as the ratio of urine protein to creatinine.The Clinical Endpoint Committee reviewed every case.MMFIVCMMF was not superior to IVC (p = 0.575)
28Primary Endpoint by Race ‘Other’ mostly comprises 46 black patients and 36 ‘mestizo’ (Latin American mixed race) patients.There was a consistent response to MMF across racial groups. There was more variability in response to IVC.These results are likely to be confounded by the effects of region. Most patients in the ‘Other’ group were from Latin America.28
29Primary Endpoint by Ethnicity There was similar response to MMF in Hispanic and non-Hispanic patients.There was a big difference in response rates in patients receiving IVC.Most Hispanics were from Latin America.
31Key Renal Secondary Endpoints Complete remission as defined by:return to normal serum creatinine levelproteinuria ≤500 mg/24 hrinactive urinary sedimentRemission in each one of these individual parametersAnti-dsDNA, C3, C4 and serum albumin
32Remission Rates by Renal Criteria No significant differences between groups in complete remission or by individual criteria
33Patients who experienced AE ≥10% MMF IVC Nausea27 (14.7)82 (45.6)Vomiting25 (13.6)68 (37.8)Headache38 (20.7)47 (26.1)Alopecia20 (10.9)64 (35.6)Diarrhea52 (28.3)23 (12.8)Arthralgia29 (15.8)43 (23.9)Peripheral edema35 (19.0)30 (16.7)Nasopharyngitis29 (16.1)Hypertension26 (14.1)25 (13.9)Leukopenia11 (6.0)38 (21.1)Upper respiratory tract infection17 (9.2)28 (15.6)Fever12 (6.5)Cough24 (13.0)16 (8.9)Rash19 (10.3)21 (11.7)AEs are > or = to 10%Overall, the adverse events reported were consistent with the known safety profile of both drugs.The incidence of diarrhea in the MMF group was much lower than that described in the transplant population, and only rarely led to dose reduction or withdrawal.A large number of patients in the IVC group suffered nausea and vomiting, despite the widespread use of prophylactic antiemetics.Clinically significant leukopenia is still a problem in patients treated with IVC.FURTHER INFORMATIONMore patients experienced nausea and vomiting with IVC than with MMF.More patients experienced diarrhea with MMF than with IVC.The diarrhea associated with MMF use was consistent with the known drug safety profile, as was the incidence of anemia for IVC.Leukopenia is an expected adverse event with both drugs.AEs accounted for 24 withdrawals in the MMF group (12 due to infections) compared with 13 in the IVC group (4 due to infections).‘Abdominal pain’ and ‘abdominal pain upper’ are separate preferred terms in the adverse events listings.33
34Summary of DeathsMMF group: 2 deaths in Argentina, 6 in China, and 1 in MalaysiaIVC group: 2 deaths in the USA, 2 in China, and 1 in the UKMMF group: 7 deaths were due to infections and none due to SLEIVC group: 2 deaths due to infections, 2 due to SLEThese were the primary causes of deaths given by the investigators; however, analysis of the cases suggested that there were complex interactions of complications of immunosuppression and disease at play.Just over half of all the deaths were in Asia, and two of the deaths from sepsis occurred a day after the initiation of therapy, suggesting severe underlying diseaseA post-hoc analysis of possible contributory factors to the deaths and adverse events concluded that there were no associations ofrace/ethnicityregionbody surface area, or weightwith the adverse outcomes for MMF.However baseline renal dysfunction was predictive of death, independently of treatment.FURTHER INFORMATIONIn the MMF group, 7 deaths were related to study drug and 3 were related to lupus, compared with 2 related to study drug and 3 related to lupus in the IVC group.No associations of race/ethnicity, region, body surface area, or weight with the adverse outcomes for MMF.Overall, patients from Asia suffered the fewest infections in both groups, but those infections more likely to result in hospitalization or death.Baseline renal dysfunction was predictive of death, independently of treatment.
35SummaryStudy did not meet its primary objective of showing that MMF was superior to IVCResponse rates with MMF were consistent across racial, ethnic, and regional groupsResponse rates lower with IVC compared with MMF in non-Caucasian, non-Asian patients, ethnically Hispanic patients, and patients in Latin AmericaAE profiles for MMF and IVC were broadly similar over 24 weeks, and consistent with previous reportsOverall incidence of adverse events and infections similar between racial groupsOngoing maintenance phase compares MMF with azathioprine for up to 3 yearsAs response to both treatments was comparable, the study endpoint was not met.However, MMF appeared more consistently effective across racial/ethnic and geographical groups than IVC.35
36Degree and durability of remission not optimal for many patients Many patients fail to achieve complete remissionLess than 50% survival without end-stage renal disease (ESRD) at 10 years in absence of complete remission.Significant rates of renal flare despite maintenance therapyAdverse events can limit effective dosing of common maintenance therapies for lupus nephritisHigh cost burden associated with lupus nephritisCosts escalate with degree of renal damage
37Many Patients Do Not Achieve Complete Remission Following Induction Prevalence of Complete Remission in Lupus Nephritis Following Induction Therapy (24 weeks)Percentage of PatientsN = 140(Intent-to-treat analysis)Mycophenolate Mofetil or Intravenous Cyclophosphamide for Lupus NephritisEllen M. Ginzler, M.D., M.P.H., Mary Anne Dooley, M.D., M.P.H., Cynthia Aranow, M.D., Mimi Y. Kim, Sc.D.,Jill Buyon, M.D., Joan T. Merrill, M.D., Michelle Petri, M.D., M.P.H., Gary S. Gilkeson, M.D.,Daniel J. Wallace, M.D., Michael H. Weisman, M.D., and Gerald B. Appel, M.D.backgroundSince anecdotal series and small, prospective, controlled trials suggest that mycophenolate mofetil may be effective for treating lupus nephritis, larger trials are desirable.methodsWe conducted a 24-week randomized, open-label, noninferiority trial comparing oral mycophenolate mofetil (initial dose, 1000 mg per day, increased to 3000 mg per day) with monthly intravenous cyclophosphamide (0.5 g per square meter of body-surface area, increased to 1.0 g per square meter) as induction therapy for active lupus nephritis. A change to the alternative regimen was allowed at 12 weeks in patients who did not have an early response. The study protocol specified adjunctive care and the use and tapering of corticosteroids. The primary end point was complete remission at 24 weeks (normalization of abnormal renal measurements and maintenance of baseline normal measurements). A secondary end point was partial remission at 24 weeks.ResultsOf 140 patients recruited, 71 were randomly assigned to receive mycophenolate mofetil and 69 were randomly assigned to receive cyclophosphamide. At 12 weeks, 56 patients receiving mycophenolate mofetil and 42 receiving cyclophosphamide had satisfactory early responses. In the intention-to-treat analysis, 16 of the 71 patients (22.5 percent) receiving mycophenolate mofetil and 4 of the 69 patients receiving cyclophosphamide (5.8 percent) had complete remission, for an absolute difference of 16.7 percentage points (95 percent confidence interval, 5.6 to 27.9 percentage points; P=0.005), meeting the prespecified criteria for noninferiority and demonstrating the superiority of mycophenolate mofetil to cyclophosphamide. Partial remission occurred in 21 of the 71 patients (29.6 percent) and 17 of the 69 patients (24.6 percent), respectively (P=0.51). Three patients assigned to cyclophosphamide died, two during protocol therapy. Fewer severe infections and hospitalizations but more diarrhea occurred among those receiving mycophenolate.ConclusionsIn this 24-week trial, mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile.Source: Ginzler et al. NEJM. 2005; 353(21)Complete remission defined as return to within 10% of normal values of serum creatinine, proteinuria, and urine sediment. Source: Ginzler et al. NEJM. 2005; 353(21)
38Importance of Maintaining Complete Remission in Lupus Nephritis Results of a long-term prospective study in patients with diffuse lupus nephritisPatient Survival Without ESRD at 10 YearsPatient survival without ESRD less than 50% at 10 years with partial remissionPercentage of Patients Surviving Without ESRDP< (CR vs PR)Value of a Complete or Partial Remission in Severe Lupus NephritisYiann E. Chen,* Stephen M. Korbet,* Robert S. Katz,* Melvin M. Schwartz,† andEdmund J. Lewis* for the Collaborative Study GroupDepartments of *Medicine and †Pathology, Rush University Medical Center, Chicago, IllinoisBackground and objectives: The value of a complete remission in severe lupus nephritis is well known but little is known about the impact of a partial remission in this patient population. The purpose of this study was to evaluate the long-term prognosis of achieving a complete or partial remission in a well-defined group of patients with severe lupus nephritis.Design, setting, participants, & measurements: In this study, 86 patients with diffuse lupus glomerulonephritis were reviewed for assessment of the value of a partial remission (50% reduction in baseline proteinuria to <1.5 g/d and <25% increase in baseline creatinine) and complete remission (proteinuria <0.33 g/d and serum creatinine <1.4 mg/dl) on outcomes compared with patients who did not attain a remission. These well-characterized patients were entered into a prospective therapeutic trial conducted by the Collaborative Study Group and were followed for more than 10 yr.Results: All biopsies showed diffuse lupus nephritis. A complete remission was attained in 37 (43%) patients, a partial remission in 21 (24%) patients, and no remission in 28 (32%) patients. Baseline clinical and serologic features were similar among the groups, but patients with a complete remission had a lower serum creatinine and chronicity index compared with patients with partial or no remission. The patient survival at 10 yr was 95% for complete remission, 76% for partial remission, and 46% for no remission. The renal survival at 10 yr was 94% for complete remission, 45% for partial remission, and 19% for no remission, and the patient survival without end-stage renal disease at 10 yr was 92% for complete remission, 43% for partial remission, and 13% for no remission.Conclusion: Even a partial remission in lupus nephritis is associated with a significantly better patient and renal survival compared with no remission.Clin J Am Soc Nephrol 3: 46–53, doi: /CJNN = 86Partial Remission: 50% reduction in baseline proteinuria to < 1.5 g/d with not more than 25% increase in baseline sCr. Complete Remission: Proteinuria < 0.33 g/d and serum creatinine < 1.4 mg/dlSource: Chen et al. Clin J Am Soc Neph. 2008; 3(1)
39Common Maintenance Therapies for Lupus Nephritis Often Do Not Prevent Renal Flare StudyContreras et al.NEJM. 2004; 350(10)Houssiau et al.A&R. 2004; 50(12)Mok et al.A&R. 2004;50(8)Patient TypePrimarily Black and Hispanic with diffuse proliferative nephritis (n=59)Primarily Caucasian with diffuse proliferative nephritis (n=89)Chinese patients with diffuse proliferative nephritis (n=189)TherapyIV CYC induction followed by maintenance with AZA, CYC, or MMF with corticosteroidsHigh or low dose IV CYC following by maintenance AZA with corticosteroidsCYC followed by maintenance AZA with corticosteroids*Definition of Renal FlareDoubling of urine protein / Cr ratio or sCr increase of 50%Severe renal flare not responding to increase in glucocorticoid doseUrine protein (P) > 2 g/d after complete response OR doubling of P after partial responseOR recurrent active sediment regardless of PDuration of Follow-up (Median)25 – 30 months **41 months36 monthsRenal Flare(% patients)29%28%See appendix for copies of the abstracts* Maintenance therapy given at physician discretion; 75% of patients received AZA maintenance therapy.