A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis

We performed a post hoc analysis of the Belimumab International Study in Lupus Nephritis (BLISS-LN), a Phase 3, multinational, double-blind, 104-week trial, in which 448 patients with lupus nephritis were randomized to receive intravenous belimumab 10 mg/kg or placebo with standard therapy (cyclophosphamide/azathioprine or mycophenolate mofetil). Add-on belimumab was found to be most effective in improving the primary efficacy kidney response and complete kidney response in patients with proliferative lupus nephritis and a baseline urine protein/creatinine ratio under 3 g/g. However, there was no observed improvement in the kidney response with belimumab treatment in patients with lupus nephritis and sub-epithelial deposits or with a baseline protein/creatinine ratio of 3 g/g or more. Belimumab significantly reduced the risk of kidney-related events or death and lupus nephritis flare in the overall population. Belimumab reduced the risk of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) versus standard treatment alone and attenuated the annual rate of eGFR decline in patients who remained on-study. Thus, our data suggest that the addition of belimumab to standard therapy could attenuate the risk of lupus nephritis flare and eGFR decline in a broad spectrum of patients with lupus nephritis. We performed a post hoc analysis of the Belimumab International Study in Lupus Nephritis (BLISS-LN), a Phase 3, multinational, double-blind, 104-week trial, in which 448 patients with lupus nephritis were randomized to receive intravenous belimumab 10 mg/kg or placebo with standard therapy (cyclophosphamide/azathioprine or mycophenolate mofetil). Add-on belimumab was found to be most effective in improving the primary efficacy kidney response and complete kidney response in patients with proliferative lupus nephritis and a baseline urine protein/creatinine ratio under 3 g/g. However, there was no observed improvement in the kidney response with belimumab treatment in patients with lupus nephritis and sub-epithelial deposits or with a baseline protein/creatinine ratio of 3 g/g or more. Belimumab significantly reduced the risk of kidney-related events or death and lupus nephritis flare in the overall population. Belimumab reduced the risk of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) versus standard treatment alone and attenuated the annual rate of eGFR decline in patients who remained on-study. Thus, our data suggest that the addition of belimumab to standard therapy could attenuate the risk of lupus nephritis flare and eGFR decline in a broad spectrum of patients with lupus nephritis. see commentary on page 224 see commentary on page 224 Lupus nephritis (LN) is one of the most severe organ manifestations of systemic lupus erythematosus.1Anders H.J. Saxena R. Zhao M.H. et al.Lupus nephritis.Nat Rev Dis Primers. 2020; 6: 7Crossref PubMed Scopus (110) Google Scholar Cyclophosphamide (CYC), azathioprine (AZA), and mycophenolate mofetil (MMF) are routinely used as standard therapies (STs) alongside glucocorticoids for the treatment of LN,1Anders H.J. Saxena R. Zhao M.H. et al.Lupus nephritis.Nat Rev Dis Primers. 2020; 6: 7Crossref PubMed Scopus (110) Google Scholar,2Parikh S.V. Almaani S. Brodsky S. Rovin B.H. Update on lupus nephritis: core curriculum 2020.Am J Kidney Dis. 2020; 76: 265-281Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar but kidney response rates remain low.3Almaani S. Meara A. Rovin B.H. Update on lupus nephritis.Clin J Am Soc Nephrol. 2017; 12: 825-835Crossref PubMed Scopus (344) Google Scholar Up to 25% of patients who achieve remission have a flare within 3 to 4 years,4Dooley M.A. Jayne D. Ginzler E.M. et al.Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis.N Engl J Med. 2011; 365: 1886-1895Crossref PubMed Scopus (426) Google Scholar,5Houssiau F.A. D’Cruz D. Sangle S. et al.Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial.Ann Rheum Dis. 2010; 69: 2083-2089Crossref PubMed Scopus (354) Google Scholar and up to 30% of patients progress to end-stage kidney disease (ESKD) and require kidney replacement therapy within 10 to 15 years of diagnosis.6Mahajan A. Amelio J. Gairy K. et al.Systemic lupus erythematosus, lupus nephritis and end-stage renal disease: a pragmatic review mapping disease severity and progression.Lupus. 2020; 29: 1011-1020Crossref PubMed Scopus (15) Google Scholar,7Tektonidou M.G. Dasgupta A. Ward M.M. Risk of end-stage renal disease in patients with lupus nephritis, 1971-2015: a systematic review and Bayesian meta-analysis.Arthritis Rheumatol. 2016; 68: 1432-1441Crossref PubMed Scopus (179) Google Scholar Belimumab is a recombinant human IgG1λ monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS) and is approved for patients 5 years or older with active autoantibody-positive systemic lupus erythematosus.8GlaxoSmithKlineHighlights of prescribing information: BENLYSTA (belimumab).https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Benlysta/pdf/BENLYSTA-PI-MG-IFU.PDFGoogle Scholar To address unmet needs in patients with LN, the Belimumab International Study in Lupus Nephritis (BLISS-LN) was conducted to determine whether the addition of belimumab to standard immunosuppressive regimens improved kidney outcomes compared with ST plus placebo. The results of BLISS-LN were recently reported9Furie R. Rovin B.H. Houssiau F. et al.Two-year, randomized, controlled trial of belimumab in lupus nephritis.N Engl J Med. 2020; 383: 1117-1128Crossref PubMed Scopus (169) Google Scholar and supported belimumab approval for the treatment of adults with active LN in the United States and the European Union.8GlaxoSmithKlineHighlights of prescribing information: BENLYSTA (belimumab).https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Benlysta/pdf/BENLYSTA-PI-MG-IFU.PDFGoogle Scholar BLISS-LN was the first successful phase 3 randomized controlled trial in patients with LN to show superior kidney outcomes and a similar safety profile after the addition of a novel biologic drug to ST. The design of the trial had many unique features, including an ST regimen chosen by each site’s principal investigator; a very strict glucocorticoid tapering and maintenance schedule; 2-year duration; unique end point criteria for the assessment of kidney response; and evaluation of kidney-related events associated with long-term progression to kidney failure.9Furie R. Rovin B.H. Houssiau F. et al.Two-year, randomized, controlled trial of belimumab in lupus nephritis.N Engl J Med. 2020; 383: 1117-1128Crossref PubMed Scopus (169) Google Scholar In addition to BLISS-LN, other novel therapies are being evaluated for LN treatment. Despite these latest positive advances, the question remains how effective the emerging therapies will be in different subpopulations of patients with LN and in preserving long-term kidney function. Given the considerable number of patients who progress to ESKD,7Tektonidou M.G. Dasgupta A. Ward M.M. Risk of end-stage renal disease in patients with lupus nephritis, 1971-2015: a systematic review and Bayesian meta-analysis.Arthritis Rheumatol. 2016; 68: 1432-1441Crossref PubMed Scopus (179) Google Scholar,10Chen Y.E. Korbet S.M. Katz R.S. et al.Collaborative Study GroupValue of a complete or partial remission in severe lupus nephritis.Clin J Am Soc Nephrol. 2008; 3: 46-53Crossref PubMed Scopus (190) Google Scholar this is a particularly important concern. To investigate this question for belimumab, secondary and exploratory analyses of BLISS-LN were performed, focusing on primary and secondary efficacy end points in different subgroups and on other kidney outcomes directly relevant to long-term kidney health and survival. The results of these analyses are reported here. BLISS-LN (GlaxoSmithKline Study 114054; ClinicalTrials.gov identifier NCT01639339) was a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial designed to assess the efficacy and safety of belimumab plus ST (CYC/AZA or MMF) in adult patients with active LN. Full methods have been published.9Furie R. Rovin B.H. Houssiau F. et al.Two-year, randomized, controlled trial of belimumab in lupus nephritis.N Engl J Med. 2020; 383: 1117-1128Crossref PubMed Scopus (169) Google Scholar The study was conducted between July 2012 and July 2019 and randomized 448 patients from 107 sites in 21 countries. Eligible patients were 18 years or older with autoantibody-positive systemic lupus erythematosus as per updated American College of Rheumatology classification criteria.11Hochberg M.C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.Arthritis Rheum. 1997; 40: 1725Crossref PubMed Scopus (8497) Google Scholar In addition, patients had a urine protein/creatinine ratio (uPCR) of ≥1 and biopsy-confirmed International Society of Nephrology and the Renal Pathology Society 2003–defined12Weening J.J. D’Agati V.D. Schwartz M.M. et al.The classification of glomerulonephritis in systemic lupus erythematosus revisited.Kidney Int. 2004; 65: 521-530Abstract Full Text Full Text PDF PubMed Scopus (1041) Google Scholar class III or IV LN with or without coexisting class V LN or pure class V LN within 6 months before or during screening. Only patients with biopsy specimens showing active lesions or active and chronic lesions were enrolled. Key exclusion criteria were dialysis or B cell–targeted therapy (including belimumab) within the preceding year, receipt of CYC induction therapy within 3 months before the start of the trial, previous failures of both MMF and CYC induction therapy, and an estimated glomerular filtration rate (eGFR) of <30 ml/min per 1.73 m2 of body surface area. Patients were free to withdraw from treatment at any time during the study. Of note, even if treatment was discontinued prematurely, patients were encouraged to remain in the study and continue with assessments up to week 104. Patients were randomized (1:1) to receive belimumab 10 mg/kg i.v. or placebo as an add-on to ST, stratified by induction regimen and race. Treatment was administered on days 1 (baseline), 15, and 29 and every 28 days thereafter to week 100, with final assessments at week 104. Within 60 days before randomization, patients initiated standard induction therapy of CYC followed by maintenance with AZA, or induction and maintenance with MMF, according to the choice of the investigator. High-dose glucocorticoids were administered as part of the induction regimen but had to be tapered to ≤10 mg/d by week 24. Short-term low-dose rescue treatment was allowed until week 76 for reasons other than LN, and no increase in glucocorticoid dose was permitted between week 76 and week 104. The primary end point of BLISS-LN was the primary efficacy renal response (PERR) at week 104. Key secondary end points included complete renal response (CRR) at week 104, PERR at week 52, and time to kidney-related event or death. The secondary and post hoc analyses reported here investigated PERR, CRR, and time to kidney-related event or death in study subgroups, along with the following outcomes predictive of long-term kidney health and survival: time to first LN flare, time to a confirmed 30% or 40% decline in eGFR, sustained 30% and 40% decline in eGFR, and eGFR slope—which were performed in the overall study population and subgroups. Study subgroups included LN histologic class (class III or IV, class III + V or IV + V, and pure class V), ST regimen (CYC/AZA or MMF), and baseline proteinuria level defined by nephrotic range proteinuria threshold (uPCR of ≥3 g/g or <3 g/g). Proteinuria was measured using uPCR, and eGFR was measured using the Modification of Diet in Renal Disease formula.13Levey A.S. Coresh J. Greene T. et al.Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values.Clin Chem. 2007; 53: 766-772Crossref PubMed Scopus (1395) Google Scholar Patients who achieved PERR had a uPCR of ≤0.7 g/g with an eGFR no less than 20% below the preflare value or ≥60 ml/min per 1.73 m2 of body surface area and did not receive rescue therapy resulting in treatment failure. Patients who achieved CRR had a uPCR of <0.5 g/g with an eGFR no less than 10% below the preflare value or ≥90 ml/min per 1.73 m2 of body surface area and did not receive rescue therapy resulting in treatment failure. Time to kidney-related event or death was defined as the time from baseline to occurrence of one of the following: ESKD, doubling of serum creatinine, increased proteinuria and/or impaired kidney function, kidney disease–related treatment failure, or death for any cause. LN flares were assessed from week 24, by when all the patients had completed induction therapy and tapered glucocorticoids to ≤10 mg/d. LN flares were defined as (i) impaired kidney function (i.e., reproducible eGFR decrease of >20% from week 24) accompanied by proteinuria (uPCR of >1 g/g) and/or cellular casts (red blood cells, white blood cells in the absence of infection, or both), (ii) increase in proteinuria compared with week 24, or (iii) treatment failure due to kidney disease–related intake of prohibited medications. Increase in proteinuria was defined as an increase in uPCR of >1 if week 24 uPCR was <0.2 g/g, uPCR of >2.0 g/g if week 24 uPCR was 0.2 to 1 g/g, or as a doubling of uPCR if week 24 uPCR was >1 g/g. A subgroup analysis of LN flares in patients who achieved PERR at week 24 and patients with week 24 uPCR ≤ 0.5 g/g was also performed. The analysis included only patients who were on treatment at week 24. Time to confirmed eGFR decline of 30% and 40% were measured from day 1 and analyzed using either only on-treatment data or all data. The first analysis included all eGFR measurements obtained while patients received treatment (“on treatment”), in which data from patients who discontinued belimumab or placebo or withdrew from the study were censored from the earliest treatment discontinuation or study withdrawal time point. The second analysis included all eGFR measurements obtained while patients remained enrolled in the study (on study), even if they prematurely discontinued belimumab or placebo, with study withdrawal leading to censoring from that time point. Sustained 30% and 40% decline in eGFR was defined as a 30% and 40% decrease in eGFR from baseline before withdrawal and confirmed by the last 2 eGFR values in the study. The annual rate of eGFR decline was evaluated as a chronic slope from week 24 to account for acute effects of the LN flare and induction therapy on kidney function early in the study.14Levey A.S. Gansevoort R.T. Coresh J. et al.Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in Collaboration with the US Food and Drug Administration and European Medicines Agency.Am J Kidney Dis. 2020; 75: 84-104Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar Like the time to confirmed eGFR decline, this analysis was performed using both the on-treatment and on-study data, but similar to the LN flare analysis, it included only patients who remained on treatment at week 24. Efficacy end points were analyzed using the modified intention-to-treat population that included 223 patients in each treatment group. Two patients in the total randomized population (n = 448) were excluded from the modified intention-to-treat population because of compliance issues at the research site. In general, statistical models controlled for race (Black African ancestry vs. non-Black African ancestry), induction regimen (CYC vs. MMF), baseline uPCR, and baseline eGFR. In the derivation of PERR and CRR, treatment (belimumab or placebo) discontinuation, study withdrawal, or treatment failure were imputed as “no response.” In the derivation of the time to kidney-related event or death, data were censored after discontinuation of treatment, study withdrawal, or treatment failure unrelated to a kidney event. PERR and CRR were analyzed using logistic regression models (analyses for the baseline proteinuria subgroups were post hoc). Time to renal-related event or death was analyzed using a Cox proportional hazards regression model (subgroup analyses were post hoc except for the analysis according to induction regimen, which was prespecified in the study protocol). The post hoc end point of time to first LN flare from week 24 was analyzed using a Cox proportional hazards model adjusted for induction regimen, race, week 24 uPCR, and week 24 eGFR. The annual rate of eGFR decline from week 24 (post hoc analysis) was estimated from a linear mixed model consisting of treatment group (belimumab vs. placebo), analysis visit (study week), and their interaction as well as random intercept and slope at the patient level. The covariance structure for the random intercept and slope was unstructured and heterogeneous for treatment groups. The post hoc end points of time to 30% and 40% decline in eGFR from baseline were analyzed with Cox proportional hazards models adjusted for induction regimen, race, baseline uPCR, and baseline eGFR. Sustained 30% and 40% decline in eGFR (post hoc analysis) were analyzed using logistic regression models with the following covariates: treatment group, induction regimen, race, baseline uPCR, and baseline eGFR. Analyses other than PERR, CRR, and time to death or renal-related event as specified above were post hoc and results should only be regarded as descriptive in nature. Additionally, the study was not powered to investigate subgroups and therefore any analyses by subgroup should be regarded as descriptive. The baseline characteristics of the BLISS-LN modified intention-to-treat population were reported previously9Furie R. Rovin B.H. Houssiau F. et al.Two-year, randomized, controlled trial of belimumab in lupus nephritis.N Engl J Med. 2020; 383: 1117-1128Crossref PubMed Scopus (169) Google Scholar and are summarized in Table 1. More than half of the patients (258 [57.8%]) had class III or IV LN, 116 (26.0%) had class III + V or class IV + V LN, and 72 (16.1%) had pure class V LN. The majority of patients (82.5%, n = 368) initiated induction therapy within 4 weeks of randomization, with more than half (57.6%, n = 257) starting it within 2 weeks of day 1. More patients received induction therapy with MMF than with CYC (328 [73.5%] vs. 118 [26.5%], respectively). The mean baseline uPCR was 3.38 g/g in patients with class III or IV LN, 3.42 g/g in patients with class III + V or class IV + V LN, and 3.22 g/g in patients with pure class V LN. A total of 183 (41.0%) patients had a uPCR of ≥3 g/g at baseline. The mean eGFR was 100.5 ± 40.2 ml/min per 1.73 m2.Table 1Baseline characteristics (mITT population)CharacteristicPlacebo (n = 223)Belimumab 10 mg/kg i.v. (n = 223)Total (N = 446)Female196 (87.9)197 (88.3)393 (88.1)Age, yr33.1 ± 10.633.7 ± 10.733.4 ± 10.7RaceaPatients were counted in only 1 category. Asian109 (48.9)114 (51.1)223 (50.0) White75 (33.6)73 (32.7)148 (33.2) Black African ancestry31 (13.9)30 (13.5)61 (13.7) American Indian or Alaska Native6 (2.7)4 (1.8)10 (2.2) Multiple2 (0.9)2 (0.9)4 (0.9)SLE disease duration,bDuration was defined as (date of the first dose – diagnosis date + 1)/365.25 yr. yr3.3 (0.2–8.0)3.3 (0.3–8.1)3.3 (0.2–8.1)LN disease duration,bDuration was defined as (date of the first dose – diagnosis date + 1)/365.25 yr. yr0.2 (0.1–3.4)0.2 (0.1–3.3)0.2 (0.1–3.3)Induction regimen CYC59 (26.5)59 (26.5)118 (26.5) MMF164 (73.5)164 (73.5)328 (73.5)Kidney biopsy class III or IV132 (59.2)126 (56.5)258 (57.8) III and V or IV and V55 (24.7)61 (27.4)116 (26.0) V36 (16.1)36 (16.1)72 (16.1)uPCR at screening, g/g4.3 (3.9)3.8 (2.6)4.1 (3.3) ≥3117 (52.5)119 (53.4)236 (52.9)uPCR at baseline, g/g3.5 (3.6)3.2 (2.7)3.4 (3.2) ≥392 (41.3)91 (40.8)183 (41.0)eGFR at baseline, ml/min per 1.73 m2101.0 (42.7)100.0 (37.7)100.5 (40.2) ≥60182 (81.6)190 (85.2)372 (83.4) ≥90133 (59.6)131 (58.7)264 (59.2)CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate; LN, lupus nephritis; mITT, modified intention-to-treat; MMF, mycophenolate mofetil; SLE, systemic lupus erythematosus; uPCR, urine protein/creatinine ratio.Data are expressed as mean ± SD, median (interquartile range), or n (%).a Patients were counted in only 1 category.b Duration was defined as (date of the first dose – diagnosis date + 1)/365.25 yr. Open table in a new tab CYC, cyclophosphamide; eGFR, estimated glomerular filtration rate; LN, lupus nephritis; mITT, modified intention-to-treat; MMF, mycophenolate mofetil; SLE, systemic lupus erythematosus; uPCR, urine protein/creatinine ratio. Data are expressed as mean ± SD, median (interquartile range), or n (%). Of the 446 patients in the modified intention-to-treat population, 278 (62.3%) completed the investigational treatment through to the scheduled last dose at week 100 (146 [65.5%] and 132 [59.2%] patients randomized to belimumab and placebo, respectively) (Supplementary Figure S1). Including patients who discontinued treatment prematurely, 355 patients (79.6%) completed the study (186 [83.4%] and 169 [75.8%] in the belimumab and placebo groups, respectively; Supplementary Figure S1). The results of PERR and CRR at week 104 in the overall study population and in subgroups by ST regimens have been published.9Furie R. Rovin B.H. Houssiau F. et al.Two-year, randomized, controlled trial of belimumab in lupus nephritis.N Engl J Med. 2020; 383: 1117-1128Crossref PubMed Scopus (169) Google Scholar Because BLISS-LN enrolled patients with proliferative and membranous forms of LN, including pure class V LN, a subgroup analysis was performed to evaluate whether response to therapy differed by histologic LN class. These data suggest that the overall increase in PERR and CRR after the addition of belimumab was mainly due to patients with a proliferative histologic component (Figure 1). There was no observed treatment difference for PERR or CRR in patients with pure class V LN. As this was a small subgroup, it is difficult to draw definitive conclusions about efficacy. Overall, the risk of having a kidney-related event or death during BLISS-LN was significantly reduced by belimumab treatment.9Furie R. Rovin B.H. Houssiau F. et al.Two-year, randomized, controlled trial of belimumab in lupus nephritis.N Engl J Med. 2020; 383: 1117-1128Crossref PubMed Scopus (169) Google Scholar Kidney-related events were mainly increases in proteinuria, decreases in kidney function, or both or kidney-related treatment failure.9Furie R. Rovin B.H. Houssiau F. et al.Two-year, randomized, controlled trial of belimumab in lupus nephritis.N Engl J Med. 2020; 383: 1117-1128Crossref PubMed Scopus (169) Google Scholar When analyzed by ST regimen and LN class, the results were directionally consistent with the overall population results, suggesting positive effects of belimumab in each subgroup (Figure 2). BLISS-LN had a treatment duration of >2 years, presenting the opportunity to evaluate the effects of belimumab on the LN flare. During the last 18 months of the study, 28 of 194 (14.4%) and 51 of 196 (26.0%) patients had at least 1 LN flare while receiving belimumab or placebo, respectively. Belimumab reduced the risk of an LN flare by 55% relative to placebo (hazard ratio [95% confidence interval] 0.45 [0.28–0.72]; P = 0.0008) (Figure 3). Excluding treatment failure due to kidney disease–related intake of prohibited medications from the LN flare definition (24 fewer patients have flares), belimumab reduced the risk of an LN flare at any time relative to placebo by 59% (hazard ratio [95% confidence interval] 0.41 [0.23–0.73]; P = 0.0023). Consistent with the overall population, a reduction in the risk of an LN flare with belimumab was evident in both ST groups and across all LN classes (Figure 4). Similar trends favoring belimumab were observed in patients who achieved either PERR or uPCR ≤ 0.5 g/g at week 24 (Supplementary Table S1).Figure 4Time to first lupus nephritis (LN) flare from week 24 by standard therapy regimen and LN classa (modified intention-to-treat population). aAnalyses were post hoc. bPatients who discontinued the study treatment, withdrew from the study, are lost to follow-up, or have treatment failure not related to kidney disease were censored on the date of the event. Kidney-related treatment failure is considered an event. Patients who completed the study were censored at week 104. cPlacebo, n = 196; belimumab, n = 194. dCyclophosphamide (CYC)/azathioprine (AZA), placebo, n = 51; belimumab, n = 49; mycophenolate mofetil (MMF), placebo, n = 145; belimumab, n = 145. eClass III or IV, placebo, n = 116; belimumab, n = 112; class III + V or IV + V, placebo, n = 48; belimumab, n = 52; class V, placebo, n = 32; belimumab, n = 30. CI, confidence interval.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The slope of eGFR was assessed between week 24 and week 104 (Table 2). The annual rate of decline in eGFR appeared to be less in the belimumab-treated group than in the placebo group in both the on-treatment and on-study analyses (Table 2).Table 2eGFR slope from week 24 to week 104aAnalyses were post hoc. (mITT population)VariableOn treatmentbData from after treatment discontinuation were excluded.On studycIncludes all available data for patients on treatment at week 24.Placebo (n = 223)Belimumab 10 mg/kg i.v. (n = 223)Placebo (n = 223)Belimumab 10 mg/kg i.v. (n = 223)Patients with ≥1 eGFR value from week 24, n198196198196Patients with eGFR value at week 104, n128140163173eGFR (SE) at week 24dStatistics are from a linear mixed model consisting of treatment group (belimumab vs. placebo), analysis visit (weeks), and their interaction as well as random intercept and slope at the patient level. The covariance structure for the random intercept and slope is unstructured and heterogeneous for treatment groups.106.6 (2.49)109.4 (2.36)106.8 (2.55)109.5 (2.39)eGFR slope (SE), ml/min per 1.73 m2 per yrdStatistics are from a linear mixed model consisting of treatment group (belimumab vs. placebo), analysis visit (weeks), and their interaction as well as random intercept and slope at the patient level. The covariance structure for the random intercept and slope is unstructured and heterogeneous for treatment groups.−3.18 (1.10)−0.99 (0.77)−5.72 (1.46)−2.12 (0.97)eGFR slope difference vs. placebo (SE)dStatistics are from a linear mixed model consisting of treatment group (belimumab vs. placebo), analysis visit (weeks), and their interaction as well as random intercept and slope at the patient level. The covariance structure for the random intercept and slope is unstructured and heterogeneous for treatment groups.2.19 (1.34)3.61 (1.76)95% CIdStatistics are from a linear mixed model consisting of treatment group (belimumab vs. placebo), analysis visit (weeks), and their interaction as well as random intercept and slope at the patient level. The covariance structure for the random intercept and slope is unstructured and heterogeneous for treatment groups.−0.45 to 4.840.15 to 7.06P valuedStatistics are from a linear mixed model consisting of treatment group (belimumab vs. placebo), analysis visit (weeks), and their interaction as well as random intercept and slope at the patient level. The covariance structure for the random intercept and slope is unstructured and heterogeneous for treatment groups.0.10410.0407CI, confidence interval; eGFR, estimated glomerular filtration rate; mITT, modified intention-to-treat; SE, standard error.a Analyses were post hoc.b Data from after treatment discontinuation were excluded.c Includes all available data for patients on treatment at week 24.d Statistics are from a linear mixed model consisting of treatment group (belimumab vs. placebo), analysis visit (weeks), and their interaction as well as random intercept and slope at the patient level. The covariance structure for the random intercept and slope is unstructured and heterogeneous for treatment groups. Open table in a new tab CI, confidence interval; eGFR, estimated glomerular filtration rate; mITT, modified intention-to-treat; SE, standard error. In both the on-treatment and on-study analyses, belimumab reduced the risk of having a 30% and 40% decline in eGFR during 104 weeks relative to placebo (Table 3). Sustained 30% and 40% decline in eGFR (as confirmed by the last 2 observed eGFR measurements) was less commonly reported with belimumab treatment relative to placebo (Table 4). These eGFR thresholds are considered predictors of future kidney insufficiency or failure.15Levey A.S. Inker L.A. Matsushita K. et al.GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.Am J Kidney Dis. 2014; 64: 821-835Abstract Full Text Full Text PDF PubMed Scopus (308) Google ScholarTable 3Time to 30% and 40% decline in eGFRaAnalyses were post hoc. between baseline and week 104 (mITT population)VariableOn treatmentbPatients who discontinued treatment and/or withdrew from the study were censored from the first occurrence.On studycPatients who withdrew from the study were censored from that point.Placebo (n = 223)Belimumab 10 mg/kg i.v. (n = 223)Placebo (n = 223)Belimumab 10 mg/kg i.v. (n = 223)30% decrease in eGFR n (%)28 (12.6)15 (6.7)38 (17.0)19 (8.5) HR (9