Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies
Authors: Christoph Licht, Larry A. Greenbaum, Petra Muus, Sunil Babu, Camille L. Bedrosian, David J. Cohen, Yahsou Delmas, Kenneth Douglas, Richard R. Furman, Osama A. Gaber, Timothy Goodship, Maria Herthelius, Maryvonne Hourmant, Christophe M. Legendre, Giuseppe Remuzzi, Neil Sheerin, Antonella Trivelli, Chantal Loirat
Journal: Kidney International (2015)

Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m2 or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up. Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m2 or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up. Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, and possibly life-threatening disease of chronic, uncontrolled complement activation, which affects patients of all ages.1Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google Scholar aHUS is caused by dysregulation of the complement alternative pathway, leading to persistent cleavage of complement protein C5, generation of proinflammatory C5a and lytic C5b proteins, and the formation of the membrane attack complex (C5b–9), which in turn leads to endothelial cell activation, injury, and death.1Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google Scholar,2Zipfel P.F. Heinen S. Skerka C. Thrombotic microangiopathies: new insights and new challenges.Curr Opin Nephrol Hypertens. 2010; 19: 372-378Crossref PubMed Scopus (42) Google Scholar,3Licht C. Pluthero F.G. Li L. et al.Platelet-associated complement factor H in healthy persons and patients with atypical HUS.Blood. 2009; 114: 4538-4545Crossref PubMed Scopus (61) Google Scholar Patients with complement alternative pathway dysregulation are at lifelong risk of thrombocytopenia, hemolysis, and renal impairment that may also occur with extrarenal (i.e., neurological, cardiovascular, pulmonary, and gastrointestinal) organ damage.1Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google Scholar,4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar,5Azukaitis K. Loirat C. Malina M. et al.Macrovascular involvement in a child with atypical hemolytic uremic syndrome.Pediatr Nephrol. 2014; 29: 1273-1277Crossref PubMed Scopus (13) Google Scholar Mutations in complement genes (e.g., CFH, MCP, CFI, CFB, and C3) or complement factor H (CFH) autoantibodies are identified in ∼50–70% of patients with aHUS.4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar,6Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (698) Google Scholar,7Zuber J. Fakhouri F. Roumenina L.T. et al.Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies.Nat Rev Nephrol. 2012; 8: 643-657Crossref PubMed Scopus (390) Google Scholar Components of the coagulation pathway can also modulate complement activation, and abnormalities in genes encoding thrombomodulin (THBD/CD146) and plasminogen (PLG)8Delvaeye M. Noris M. De Vriese A. et al.Thrombomodulin mutations in atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 345-357Crossref PubMed Scopus (419) Google Scholar,9Bu F. Maga T. Meyer N.C. et al.Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome.J Am Soc Nephrol. 2014; 25: 55-64Crossref PubMed Scopus (160) Google Scholar have been identified in small numbers of patients. Rare cases of thrombotic microangiopathy (TMA) are caused by recessive diacylglycerol kinase ε (DGKE) mutations;10Lemaire M. Fremeaux-Bacchi V. Schaefer F. et al.Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.Nat Genet. 2013; 45: 531-536Crossref PubMed Scopus (341) Google Scholar thus far, instances have been limited to infants <1 year of age, and have not been reported in adolescent- and adult-onset aHUS. Although TMA complications observed in DGKE mutation carriers indicate complement-independent pathogenesis,10Lemaire M. Fremeaux-Bacchi V. Schaefer F. et al.Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.Nat Genet. 2013; 45: 531-536Crossref PubMed Scopus (341) Google Scholar a recent report identified a consanguineous family with DGKE mutations and evidence of significantly decreased C3 levels.11Westland R. Bodria M. Carrea A. et al.Phenotypic expansion of DGKE-associated diseases.J Am Soc Nephrol. 2014; 25: 1408-1414Crossref PubMed Scopus (51) Google Scholar Plasma exchange/plasma infusion (PE/PI) has historically been used to manage aHUS, yet 67% of adult patients required dialysis or died within 3 years, with variations in outcome by genotype.6Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (698) Google Scholar Registry and observational studies have demonstrated mortality rates of 8% at the first manifestation and 11% at 3 years of follow-up in one series,6Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (698) Google Scholar and 2% in adults and 8% in children at ≥ 45 months of follow-up in another series.4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar In addition, many patients with aHUS require kidney transplantation6Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (698) Google Scholar but experience high rates (68%) of post-transplant recurrence of TMA leading to graft failure; rates vary by genotype but graft failure occurs in ∼70% within 5 years.12Le Quintrec M. Zuber J. Moulin B. et al.Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome.Am J Transplant. 2013; 13: 663-675Crossref PubMed Scopus (189) Google Scholar Thus, although PE/PI may temporarily maintain hematologic parameters, it does not inhibit the underlying complement-mediated pathogenic mechanism of TMA,4Fremeaux-Bacchi V. Fakhouri F. Garnier A. et al.Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults.Clin J Am Soc Nephrol. 2013; 8: 554-562Crossref PubMed Scopus (481) Google Scholar,6Noris M. Caprioli J. Bresin E. et al.Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.Clin J Am Soc Nephrol. 2010; 5: 1844-1859Crossref PubMed Scopus (698) Google Scholar,13Loirat C. Garnier A. Sellier-Leclerc A.L. et al.Plasmatherapy in atypical hemolytic uremic syndrome.Semin Thromb Hemost. 2010; 36: 673-681Crossref PubMed Scopus (73) Google Scholar,14Ariceta G. Besbas N. Johnson S. et al.Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome.Pediatr Nephrol. 2009; 24: 687-696Crossref PubMed Scopus (266) Google Scholar it does not block the terminal complement pathway, or it does not efficiently prevent progression of tissue damage and substantial morbidity and mortality. Eculizumab (Soliris), the only approved treatment for aHUS,15US Food and Drug AdministrationSoliris [prescribing information]. Alexion Pharmaceuticals, Inc, Cheshire, CT, USA2014Google Scholar,16European Medicines AgencySoliris [summary of product characteristics]. Alexion Europe SAS, Paris, France2014Google Scholar is a humanized monoclonal antibody that binds with high affinity to the human C5 complement protein and blocks the formation of proinflammatory C5a and lytic C5b.7Zuber J. Fakhouri F. Roumenina L.T. et al.Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies.Nat Rev Nephrol. 2012; 8: 643-657Crossref PubMed Scopus (390) Google Scholar,17Rother R.P. Rollins S.A. Mojcik C.F. et al.Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria.Nat Biotechnol. 2007; 25: 1256-1264Crossref PubMed Scopus (536) Google Scholar,18Barnett A.N. Asgari E. Chowdhury P. et al.The use of eculizumab in renal transplantation.Clin Transplant. 2013; 27: E216-E229Crossref PubMed Scopus (45) Google Scholar,19Chatelet V. Fremeaux-Bacchi V. Lobbedez T. et al.Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome.Am J Transplant. 2009; 9: 2644-2645Crossref PubMed Scopus (101) Google Scholar,20Zuber J. Quintrec M.L. Krid S. et al.Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation.Am J Transplant. 2012; 12: 3337-3354Crossref PubMed Scopus (201) Google Scholar The efficacy and safety of eculizumab were demonstrated in two prospective 26-week phase 2 studies with 1-year extension phases: one in patients with aHUS with clinical evidence of progressing TMA (trial 1; N=17; ClinicalTrials.gov numbers NCT00844545 (adults) and NCT00844844 (adolescents)), and one in patients with aHUS with long duration of disease and chronic kidney damage receiving prolonged PE/PI (trial 2; N=20; ClinicalTrials.gov numbers NCT00838513 (adults) and NCT00844428 (adolescents)).21Legendre C.M. Licht C. Muus P. et al.Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.N Engl J Med. 2013; 368: 2169-2181Crossref PubMed Scopus (999) Google Scholar In both studies, eculizumab inhibited complement activation within 1 h of the first dose. Treatment resulted in significant improvements in platelet count and renal function by 26 weeks (primary analysis) and at the 1-year data cutoff. In addition, patients treated with eculizumab did not have additional TMA events, and PE/PI and dialysis were decreased or eliminated. Longer-term results are needed to establish the ongoing efficacy and safety of eculizumab. Here we present outcomes after 2 years of eculizumab therapy in patients with aHUS in trial 1 and trial 2. In trial 1, 17 patients (16 adults and one adolescent) with aHUS and progressing TMA were enrolled and 13 entered the extension phase (Figure 1). At the 2-year data cutoff, 11 patients remained on eculizumab (five on study drug in the trial; six transitioned to commercial eculizumab) and two had withdrawn due to worsening renal function. The median (range) duration of eculizumab exposure in trial 1 was 100 (2–145) weeks. In trial 2, 20 patients (15 adults and five adolescents) were enrolled in and completed the initial 26-week study. Nineteen patients entered the extension period and continued eculizumab treatment for ≥ 78 weeks (Figure 1). At the 2-year data cutoff, 18 patients remained on eculizumab (16 on study drug in the trial, and two transitioned to commercial eculizumab). The median (range) duration of eculizumab exposure in trial 2 was 114 (26–129) weeks. In both trials, data were not available after patients transferred to commercial eculizumab. Terminal complement activity was sufficiently inhibited at all scheduled time points over 2 years in both studies (Figure 2).Figure 2Effect of eculizumab on serum complement inhibition over 2 years of treatment in trial 1 and trial 2. Results from a pharmacodynamic assay that quantified serum complement activity by measuring the degree of hemolysis, as determined by means of a spectrophotometer. Inhibition of complement activity is indicated by 20% or lower hemolysis. Bars represent s.e.View Large Image Figure ViewerDownload (PPT) Baseline demographics and disease characteristics were previously reported and are summarized in Table 1. The median time from onset of the current clinical manifestation of aHUS to screening for the trial was 0.8 months in trial 1 and 8.6 months in trial 2. PE/PI was received by 17 patients (100%) in trial 1 and by 20 patients (100%) in trial 2 before the initiation of eculizumab, and estimated glomerular filtration rate (eGFR) was <60 ml/min per 1.73 m2 in 17 (100%) and 18 patients (90%), respectively. Six patients (35%) in trial 1 and two patients (10%) in trial 2 were on dialysis before the first dose of eculizumab; in trial 1, 5 patients (29%) were on dialysis at the initiation of therapy. The median (range) duration of dialysis during the current manifestation was 22 (1-27) days in trial 1 and 625 (120-1129) days in trial 2. In trial 1, six patients (35%) had one current kidney transplant and one patient (6%) had two transplants. In trial 2, three patients (15%) had one current transplant, three patients (15%) had two transplants, and two patients (10%) had four transplants each.Table 1Baseline demographics and disease characteristicsParameterTrial 1 (N=17)Trial 2 (N=20)Age, years, median (range)28 (17–68)28 (13–63)Female sex, n (%)12 (71)12 (60)Presence of ≥ 1 complement gene mutation and/or factor H autoantibody, n/N (%)13/17 (76)aCFH (n=4); CFI (n=3); anti-factor H autoantibodies and homozygous deletion of CFHR1 and CFHR3 (n=2); C3 (n=1); CD46 (n=1); CFH and homozygous deletion of CFHR1 and CFHR3 (n=1); and CFH, CFI, and homozygous deletion of CFHR1 and CFHR3 (n=1).14/20 (70)bCFH (n=3); CFI (n=2); CD46 (n=1); CD46 and CFI (n=1); CFB (n=1); CFH and C3 (n=1); CFI and C3 (n=1); anti-factor H autoantibodies (n=1); homozygous deletion of CFHR1 and CFHR3 (n=1); CFH and homozygous deletion of CFHR1 and CFHR3 (n=1); and anti-factor H autoantibodies, heterozygous deletion of CFHR3, and homozygous deletion of CFHR1 (n=1).Time from diagnosis of aHUS to screening, months, median (range)9.7 (0.3–235.9)48.3 (0.7–285.8)Time from current clinical presentation of aHUS to screening, months, median (range)0.8 (0.2–3.7)8.6 (1.2–45.0)Received PE/PI within 1 week before eculizumab initiation, n (%)17 (100)20 (100)Duration of PE/PI, months, median (range)0.7 (0.1–3.2)10.1 (2.4–47.0)On dialysis before the first dose of eculizumab, n/N (%)6/17 (35)cOne of the six patients who had been receiving dialysis within 8 weeks before eculizumab treatment discontinued dialysis 5 weeks before the first dose of eculizumab.2/20 (10)≥ 1 Prior kidney transplant, n/N (%)7/17 (41)8/20 (40)Platelet count, × 109/l, median (range)118 (62–161)218 (105–421)Patients with platelet count <150 × 109/l, n (%)15 (88)3 (15)LDH level, U/l, median (range)269 (134–634)200 (151–391)LDH>ULNdDefinitions of the ULN for LDH levels varied by trial, gender, and age. For adult patients, ULN was defined as 261 U/l in both trials. For adolescent patients, ULN was defined as 230-261 U/l in trial 1 and 230-290 U/l in trial 2., n (%)10 (59)4 (20)Hemoglobin level, g/l, median (range)87 (67–126)108 (79–131)Serum creatinine, μmol/l, median (range)256 (124–787)234 (106–893)eGFR, ml/min per 1.73 m2 Mean (s.d.)23 (15)31 (19) Median1928 Range5–596–72CKD stage, n (%) 1–202 (10) 3a/b5 (29)8 (40) 45 (29)6 (30) 57 (41)4 (20)EQ-5D scoreeThe EQ-5D scores range from 0 to 1, with higher scores indicating a better quality of life., median (range)0.8fn=16. (0.3-1.0)0.9 (0.2-1.0)Abbreviations: aHUS, atypical hemolytic uremic syndrome; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; EQ-5D, EuroQol 5-Dimension Questionnaire; LDH, lactate dehydrogenase; PE/PI, plasma exchange/plasma infusion; ULN, upper limit of normal.a CFH (n=4); CFI (n=3); anti-factor H autoantibodies and homozygous deletion of CFHR1 and CFHR3 (n=2); C3 (n=1); CD46 (n=1); CFH and homozygous deletion of CFHR1 and CFHR3 (n=1); and CFH, CFI, and homozygous deletion of CFHR1 and CFHR3 (n=1).b CFH (n=3); CFI (n=2); CD46 (n=1); CD46 and CFI (n=1); CFB (n=1); CFH and C3 (n=1); CFI and C3 (n=1); anti-factor H autoantibodies (n=1); homozygous deletion of CFHR1 and CFHR3 (n=1); CFH and homozygous deletion of CFHR1 and CFHR3 (n=1); and anti-factor H autoantibodies, heterozygous deletion of CFHR3, and homozygous deletion of CFHR1 (n=1).c One of the six patients who had been receiving dialysis within 8 weeks before eculizumab treatment discontinued dialysis 5 weeks before the first dose of eculizumab.d Definitions of the ULN for LDH levels varied by trial, gender, and age. For adult patients, ULN was defined as 261 U/l in both trials. For adolescent patients, ULN was defined as 230-261 U/l in trial 1 and 230-290 U/l in trial 2.e The EQ-5D scores range from 0 to 1, with higher scores indicating a better quality of life.f n=16. Open table in a new tab Abbreviations: aHUS, atypical hemolytic uremic syndrome; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; EQ-5D, EuroQol 5-Dimension Questionnaire; LDH, lactate dehydrogenase; PE/PI, plasma exchange/plasma infusion; ULN, upper limit of normal. All efficacy outcomes, calculated based on the intent-to-treat populations and defined in Table 2,22Rabin R. de Charro F. EQ-5D: a measure of health status from the EuroQol Group.Ann Med. 2001; 33: 337-343Crossref PubMed Scopus (3435) Google Scholar,23National Kidney FoundationK/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar,24Pickard A.S. Neary M.P. Cella D. Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer.Health Qual Life Outcomes. 2007; 5 ([Erratum in: Health Qual Life Outcomes. 2010;8:4]): 70Crossref PubMed Scopus (554) Google Scholar,25Rinder C.S. Rinder H.M. Smith B.R. et al.Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.J Clin Invest. 1995; 96: 1564-1572Crossref PubMed Scopus (204) Google Scholar are reported in Table 3.Table 2Definitions of primary and secondary efficacy end pointsEnd pointsDefinitionPrimary Trial 1Platelet count increase: change in platelet count from baseline to week 26 and the proportion of patients with platelet count normalization (≥ 150 × 109/l; proportion of patients with platelet count normalization sustained for at least two consecutive measurements for ≥ 4 weeks was an additional analysis) Trial 2TMA event-free status: absence of all the following for ≥ 12 consecutive weeks: (1) a decrease in platelet count of >25%, (2) plasma exchange/infusion, and (3) new dialysis Trials 1 and 2Hematologic normalization: platelet count normalization (≥ 150 × 109/l) and LDH⩽ULN sustained for at least two consecutive measurements, which span a period of ≥ 4 weeksSecondary TMA outcomesTMA event-free status (secondary in trial 1 only)TMA intervention rate: the number of PE/PIs and new dialysis (interventions/patient per day); rate during the pre-eculizumab period compared with the rate during eculizumab treatment periodComplete TMA response: hematologic normalization plus improvement in renal function (25% reduction from baseline in serum creatinine in two consecutive measurements for ≥ 4 weeks) Hematologic outcomesChange in hemoglobin ≥ 20 g/l from baselineLDH⩽ULN Renal function parametersaCriteria were required to be sustained for ≥ 2 consecutive measurements, which span a period of ≥ 4 weeks.eGFR increase ≥ 15 ml/min per 1.73 m2bFor patients on dialysis, eGFR was calculated with the creatinine value immediately before dialysis or a fixed value of 10 ml/min per 1.73 m2.. Serum creatinine decrease ≥ 25%. Improvement in proteinuria by ≥ 1 grade. Chronic kidney disease improvement of ≥ 1 stage23National Kidney FoundationK/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar Change in HRQoLChange in EQ-5D22Rabin R. de Charro F. EQ-5D: a measure of health status from the EuroQol Group.Ann Med. 2001; 33: 337-343Crossref PubMed Scopus (3435) Google Scholar using TTO value set for US population. Attainment of MID in US TTO value (0.06)24Pickard A.S. Neary M.P. Cella D. Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer.Health Qual Life Outcomes. 2007; 5 ([Erratum in: Health Qual Life Outcomes. 2010;8:4]): 70Crossref PubMed Scopus (554) Google Scholar Pharmacokinetics/pharmacodynamicsPeak and minimum serum eculizumab concentrations. Hemolysis assay25Rinder C.S. Rinder H.M. Smith B.R. et al.Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.J Clin Invest. 1995; 96: 1564-1572Crossref PubMed Scopus (204) Google Scholar AdditionalProteinuria: change in grade according to dipstick measurement (negative, trace 1+, 2+, 3+, and 4+)Urine protein-to-creatinine ratioChange in urine protein-to-creatinine ratio from baselineAbbreviations: eGFR, estimated glomerular filtration rate; EQ-5D, 5-dimension EuroQoL questionnaire; HRQoL, health-related quality of life; LDH, lactate dehydrogenase; MID, minimally important difference; PE/PI, plasma exchange/plasma infusion; TMA, thrombotic microangiopathy; TTO, time trade-off; ULN, upper limit of normal.a Criteria were required to be sustained for ≥ 2 consecutive measurements, which span a period of ≥ 4 weeks.b For patients on dialysis, eGFR was calculated with the creatinine value immediately before dialysis or a fixed value of 10 ml/min per 1.73 m2. Open table in a new tab Table 3Efficacy outcomesParameterTrial 1Trial 226-Week analysis (N=17)1-Year analysisaMedian (range) treatment duration of 64 (2–90) weeks in trial 1 and 62 (26–74) weeks in trial 2. (N=17)2-Year analysisbMedian (range) treatment duration of 100 (2–145) weeks in trial 1 and 114 (26–129) weeks in trial 2. (N=17)26-Week analysis (N=20)1-Year analysisaMedian (range) treatment duration of 64 (2–90) weeks in trial 1 and 62 (26–74) weeks in trial 2. (N=20)2-Year analysisbMedian (range) treatment duration of 100 (2–145) weeks in trial 1 and 114 (26–129) weeks in trial 2. (N=20)Primary end points Mean change from baseline in platelet count, × 109/l (95% CI)73cP<0.001 vs baseline. (40–105)91cP<0.001 vs baseline. (67–116)dData were from week 60.75cP<0.001 vs baseline. (54–96)NANANA Normalization of platelet count, n/N (%)14/17 (82)15/17 (88)15/17 (88)18/20 (90)18/20 (90)18/20 (90) TMA event-free status, n/N (%)15/17 (88)15/17 (88)15/17 (88)16/20 (80)17/20 (85)19/20 (95) Hematologic normalization, n/N (%)13/17 (76)15/17 (88)15/17 (88)18/20 (90)18/20 (90)18/20 (90)Secondary end points TMA and hematologic outcomes Complete TMA response, n/N (%)11/17 (65)13/17 (76)13/17 (76)5/20 (25)7/20 (35)11/20 (55) LDH⩽ULN, n/N (%)14/17 (82)15/17 (88)15/17 (88)19/20 (95)19/20 (95)19/20 (95) Increase in hemoglobin concentration of ≥ 20 g/l from baseline, n/N (%)11/17 (65)13/17 (76)13/17 (76)9/20 (45)10/20 (50)13/20 (65) Mean change in haptoglobin level from baseline, g/l (s.d.)0.5 (0.44)0.6 (0.41)0.9 (0.38)–0.1 (0.52)0.3 (0.61)0.5 (0.64) Renal outcomes Increase in eGFR of ≥ 15 ml/min per 1.73 m2, n/N (%)eCriteria were required to be sustained for ≥ 2 consecutive measurements, which span a period of ≥ 4 weeks.8/17 (47)9/17 (53)10/17 (59)1/20 (5)3/20 (15)8/20 (40) Decrease in serum creatinine level of ≥ 25%, n/N (%)eCriteria were required to be sustained for ≥ 2 consecutive measurements, which span a period of ≥ 4 weeks.11/17 (65)13/17 (76)13/17 (76)3/20 (15)7/20 (35)11/20 (55) Improvement in proteinuria by ≥ 1 grade, n/N (%)eCriteria were required to be sustained for ≥ 2 consecutive measurements, which span a period of ≥ 4 weeks.,fProteinuria data were not available for all patients.12/16 (75)13/16 (81)14/16 (88)6/11 (55)7/11 (64)9/11 (82) Improvement in CKD by ≥ 1 stage, n/N (%)eCriteria were required to be sustained for ≥ 2 consecutive measurements, which span a period of ≥ 4 weeks.10/17 (59)11/17 (65)12/17 (71)7/20 (35)9/20 (45)12/20 (60)Abbreviations: CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; NA, not applicable; TMA, thrombotic microangiopathy; ULN, upper limit of normal range.a Median (range) treatment duration of 64 (2–90) weeks in trial 1 and 62 (26–74) weeks in trial 2.b Median (range) treatment duration of 100 (2–145) weeks in trial 1 and 114 (26–129) weeks in trial 2.c P<0.001 vs baseline.d Data were from week 60.e Criteria were required to be sustained for ≥ 2 consecutive measurements, which span a period of ≥ 4 weeks.f Proteinuria data were not available for all patients. Open table in a new tab Abbreviations: eGFR, estimated glomerular filtration rate; EQ-5D, 5-dimension EuroQoL questionnaire; HRQoL, health-related quality of life; LDH, lactate dehydrogenase; MID, minimally important difference; PE/PI, plasma exchange/plasma infusion; TMA, thrombotic microangiopathy; TTO, time trade-off; ULN, upper limit of normal. Abbreviations: CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; NA, not applicable; TMA, thrombotic microangiopathy; ULN, upper limit of normal range. In trial 1, eculizumab treatment was associated with a significant increase in platelet count from baseline at week 26 (P<0.001), 1 year (P<0.001), and at the 2-year cutoff (P⩽0.001; Figure 3), indicating the inhibition of complement-mediated TMA throughout treatment. Platelet count was normalized in 14 patients (82%) at 26 weeks and in 15 patients (88%) at the 1- and 2-year cutoffs. Criteria for hematologic normalization were met by 13 patients (76%) at week 26 and by 15 patients (88%) at the 1- and 2-year cutoffs. The two patients who did not achieve hematologic normalization withdrew from the study within the initial 26-week treatment period. In trial 2, criteria for TMA event-free status were met by 16 patients (80%) at week 26, 17 patients (85%) at year 1, and 19 patients (95%) by the 2-year cutoff. Hematologic normalization was achieved by 18 patients (90%) at all three time points. In trial 1, 15 patients (88%) achieved TMA event-free status by 26 weeks, 1 year, and the 2-year cutoff. In comparison with a median (range) pretreatment rate of 0.88 (0.04-1.59), the median (range) TMA intervention rate decreased to 0 (0-0.31) even