No adverse events led to withdrawal of study drug during the randomized treatment period. The percentage of patients with a ≥3-point improvement in FACIT-Fatigue score was similar between the ravulizumab and eculizumab groups (37.1% vs 33.7%). Treatment effect. Kulasekararaj AG, Hill A, Rottinghaus ST, et al. The least-squares estimate of the mean (standard error) in percentage change in LDH from baseline to day 183 showed a decrease of 0.82% (3.033%) for the ravulizumab group and an increase of 8.39% (3.041%) for the eculizumab group, with a treatment difference (ravulizumab − eculizumab) of 9.21% (95% CI, −0.42% to 18.84%). Horizontal line indicates free C5 level of 0.5 µg/mL. Similarly, shifts in clinical manifestations of PNH were infrequent in both treatment groups, and no patient experienced a major adverse vascular event (Table 3). Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Please enter a term before submitting your search. [2] Treatment difference was estimated for eculizumab − ravulizumab. Aims: Ravulizumab, engineered from eculizumab, provides sustained C5 inhibition in atypical hemolytic uremic syndrome (aHUS) … To read this article in full you will need to make a payment. Clinical trial recommendations for potential Alport syndrome therapies. 6 The median time to complete TMA response was shorter in the eculizumab trial than in the current … The study consisted of a 4-week screening period followed by a 26-week randomized treatment period and an extension period during which all patients received ravulizumab for up to 2 years (supplemental Appendix, section 2; supplemental Figure 1, available on the Blood Web site). Published by Elsevier Inc. All rights reserved. BOSTON -- (BUSINESS WIRE)--May 1, 2020-- Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) today announced that the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending marketing authorization in the European Union for ULTOMIRIS ® (ravulizumab) for the treatment of patients with a body weight of 10 kg or above with atypical hemolytic uremic syndrome (aHUS) who are complement inhibitor treatment-naïve or have received SOLIRIS ® (eculizumab… In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. Twelve patients experienced serious adverse events (4 ravulizumab patients and 8 eculizumab patients). Medical writing and editorial support were provided by Lynn Brown and Traci Stuve of ApotheCom. Eligible patients must have received eculizumab treatment of ≥6 months at labeled dose before study entry, had an LDH level ≤1.5× the upper limit of normal (ULN; 246 U/L) at screening, and been vaccinated against Neisseria meningitidis <3 years before dosing or at the time of study drug initiation to reduce the risk of meningococcal infections. Copyright © 2021 Elsevier Inc. except certain content provided by third parties. Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment. Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany. In December 2018 it was given an early approval ( Alexion playing a “rare disease priority review … History of major adverse vascular events was not a component of the randomization stratification criteria. In addition, the treatment burden associated with an every-2-week dosing regimen of an IV infusion may negatively impact quality of life.20, Ravulizumab (ALXN1210) is a new complement component 5 (C5) inhibitor that produces immediate, complete, and sustained inhibition of C5 with an extended, 8-week dosing interval.21,22  Ravulizumab binds to C5 with high affinity and prevents hemolysis by inhibiting formation of C5a and C5b.23  In ravulizumab, 4 amino acid substitutions in the complementarity-determining and Fc regions of eculizumab result in enhanced endosomal dissociation of C5 and recycling to the vascular compartment through the neonatal Fc receptor pathway.22  These modifications result in a terminal half-life that is approximately fourfold longer than that of eculizumab.21,22,24. The planned sample size of ∼192 enrolled patients provided 90% power to demonstrate noninferiority of ravulizumab to eculizumab at a 1-sided α level of 0.025, a 10% dropout rate, and a noninferiority margin of 15% for percentage change in LDH from baseline to day 183. n = 50 male patients in the ravulizumab group and n = 48 male patients in the eculizumab group. If noninferiority was established for all key secondary end points, then superiority was assessed via a closed-testing procedure, using a 2-sided 0.05 test for each parameter, in the following order: percentage change in LDH, FACIT-Fatigue, breakthrough hemolysis, stabilized hemoglobin, and transfusion avoidance (supplemental Appendix, section 2). Half-life of eculizumab is 11.25-17.25 days. The most frequently reported adverse event occurring in 3% or more of patients in either treatment group was headache, which occurred in 26.8% of patients treated with ravulizumab and in 17.3% of patients treated with eculizumab. Four patients discontinued the study, 1 in the ravulizumab group (withdrawal by subject) and 3 in the eculizumab group (withdrawal by subject, lack of efficacy [3 breakthrough hemolysis events], and pregnancy). Safety analyses were performed on the safety set, defined as all patients who received at least 1 dose of ravulizumab or eculizumab. For FACIT-Fatigue, Diff (95% CI) was based on estimated difference in change from baseline with 95% CI. study were able to stop dialysis, probably due to differences in the study populations. This study was performed in accordance with the principles of the Declaration of Helsinki and the Council for International Organizations of Medical Sciences International Ethical Guidelines. Results of phase 1b/2 studies in complement-inhibitor–naive patients with PNH demonstrate that ravulizumab provides rapid and sustained reduction in complement-mediated hemolysis at dosing intervals up to 12 weeks and overall improvement of PNH-related symptomatology and quality of life.25  In the largest phase 3 study in complement-inhibitor–naive PNH patients conducted to date, ravulizumab was shown to be noninferior to eculizumab for all end points, including transfusion avoidance, lactate dehydrogenase (LDH) normalization, percentage change in LDH levels, change in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, breakthrough hemolysis, and hemoglobin stabilization.26  In this phase 3 study, we assessed the noninferiority of ravulizumab vs eculizumab in patients with PNH on stable eculizumab therapy. Similarly, mean LDH values were within the normal range at baseline and generally sustained over time (supplemental Appendix, section 3; supplemental Figure 3). The study enrolled adult patients (≥18 years of age) who had documented diagnoses of PNH, confirmed by high-sensitivity flow cytometry evaluation of red blood cells and white blood cells with granulocyte or monocyte clone size of ≥5% and who were clinically stable on eculizumab treatment. Patients randomly assigned to the eculizumab treatment group received 900 mg every 2 weeks. The pharmacodynamic analysis was performed on all patients who received at least 1 dose of study drug and who had evaluable data. doi: https://doi.org/10.1182/blood-2018-09-876805. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (Pinf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), −0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, −8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, −0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, −4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, −10.41 to 13.31]). LDH normalization is defined as proportion of patients who achieved LDH level ≤1× the ULN (246 U/L). has received consultancies, honoraria, and research funding from Alexion, Novartis, and Pfizer and research funding from Amgen. Ravulizumab achieved noninferiority compared with eculizumab (Figure 1A; Table 2) for the primary end point of percentage change in LDH, with the point estimate for treatment difference favoring ravulizumab. Until additional data/analyses are available, eculizumab remains the drug of choice The Kenward-Roger approximation was used to estimate denominator degrees of freedom. A complete list of study investigators can be found in the supplemental Appendix, section 1. We apologize for the inconvenience. developed the protocol, recruited patients, collected data, analyzed and interpreted the data, contributed to the manuscript, and approved the final version. The complete and sustained C5 inhibition associated with ravulizumab may account for the consistent results across end points. Two patients withdrew before receiving study drug, and 195 received treatment (ravulizumab, n = 97; eculizumab, n = 98) (supplemental Appendix, section 3; supplemental Figure 2). This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic … The serious infections noted in this study resolved without sequelae. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. recruited patients, collected data, analyzed and interpreted the data, contributed to the manuscript, and approved the final version; S.T.R., A.I.D., S.O., and L.S., developed the protocol, analyzed and interpreted the data, contributed to the manuscript, and approved the final version; S.L., R.W., A.G., J.W.L., E.O.G., C.I.P., and A.R. A safety review committee monitored safety, and an independent data monitoring committee monitored data for cases of meningococcal infection. All received meningococcal vaccination if they had not received it in the past 3 years. Testing of the noninferiority hypothesis is assessed by comparing the bolded limit of the 95% CI to the noninferiority margin. ALXN1210-PNH-302 was a multicenter, randomized, open-label, active-controlled study conducted in 49 centers in 11 countries (registered at www.clinicaltrials.gov as #NCT03056040 and EudraCT as #2016-002026-36, CHAMPION 302). Ravulizumab-cwvz (Ultomiris) is a second generation monoclonal antibody for aHUS made by Alexion pharmaceuticals, Inc. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS … Mean serum free C5 concentrations were suppressed to <0.5 µg/mL by the end of the first infusion and at all subsequent visits for all patients receiving ravulizumab; however, this threshold was not consistently met in the eculizumab group (Figure 3). For all efficacy end points, ravulizumab achieved noninferiority compared with eculizumab. Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial. Free C5 levels <0.5 µg/mL are associated with complete inhibition of C5 activity. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, transfusion avoidance, and stabilized hemoglobin. recruited patients, contributed to the manuscript, and approved the final version; F.A.G.-F. recruited patients, collected data, contributed to the manuscript, and approved the final version; E.B. Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome. Ravulizumab was designed to address the limitations in eculizumab therapy, particularly eculizumab’s short half-life and frequent dosing schedule. Percentage of patients achieving LDH normalization over time in the ravulizumab and eculizumab treatment groups. The key secondary end points were tested for noninferiority in a hierarchical manner provided that noninferiority was declared for the primary end point. Rates of complete thrombotic microangiopathy response were similar Accordingly, no further hierarchical testing was performed. Normal range, 11.5 to 16.0 g/dL (women) and 13.0 to 17.5 g/dL (men). [1] For the end points transfusion avoidance (TA), breakthrough hemolysis (BTH), and stabilized hemoglobin (HGB-S), Diff (95% CI) was based on estimated differences in percentage with 95% CI. Until additional data/analyses are available, eculizumab remains the drug of choice for an acute aHUS episode, whereas ravulizumab has several advantages in maintenance treatment. has received consultancies and honoraria from Alexion, Roche, and Novartis and research funding from Alexion and Roche. Key exclusion criteria included LDH value >2× the ULN in the 6 months before day 1, major adverse vascular event (supplemental Appendix, section 2) within 6 months before day 1, platelet count 30 × 109/L, absolute neutrophil count <0.5 × 109/L, body weight <40 kg at screening, history of bone marrow transplantation, and history of N meningitidis infection (supplemental Appendix, section 2). In aHUS, mutations in complement pathway genes, such as CFH, MCP (CD46), and CFI, lead to the uncontrolled activation of the alternative complement pathway, leading to thrombotic microangiopathy (TMA)or blood clots in small blood vessels. It is a Complement inhibitor too. for an acute aHUS episode, whereas ravulizumab has several advantages in maintenance Conflict-of-interest disclosure: A.G.K., A.H., R.W., F.A.G.-F., A.G., E.O.G., A.R., and S.N. Editorial review was provided by Kenneth Pomerantz of Alexion Pharmaceuticals, Inc. All analyses were performed using SAS release (SAS Institute Inc., Cary, NC), version 9.4 or higher, or other validated statistical software. Once this occurs, the resulting eculizumab… The target of ravulizumab-cwvz is the same eculizumab (Soliris) with changes … © 2020 International Society of Nephrology. Efficacy analyses were performed on the full analysis set (all patients who received at least 1 dose of ravulizumab or eculizumab). Patients randomly assigned to the ravulizumab treatment group received weight-based dosing: a loading dose on day 1 followed by maintenance doses of ravulizumab (on day 15 and every 8 weeks thereafter) (supplemental Appendix, section 2; supplemental Figure 1). Ravulizumab has recently been approved for the treat-ment of aHUS … (A) Primary end point. (A-B) A gyros-based fluorescence assay was used for patients who received ravulizumab (A), and an electrochemiluminescence immunoassay was used for patients who received eculizumab (B). S.T.R., L.S., A.I.D., and S.O. Because noninferiority was achieved for the primary end point and all 4 key secondary end points, superiority testing of percentage change in LDH was performed. Based on 2 prospective studies in mostly adults andretrospective data in children, eculizumab, a terminal complement inhibitor, isapproved for aHUS treatment. Blood 2019; 133 (6): 540–549. There were no deaths and no cases of meningococcal infection. The primary efficacy end point was hemolysis, as directly measured by percentage change in LDH levels from baseline to day 183. Long-term ACE inhibition in Alport syndrome: are the benefits worth the risks? This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. Use your society credentials to access all journal content and features. Presented at 60th annual meeting of the American Society of Hematology, San Diego, CA, 1-4 December 2018. The authors also thank the investigators of ALXN1210-PNH-302, who are listed in the supplemental Appendix, section 1. The FDA will review ravulizumab for the treatment of … (B) Secondary end point. Ravulizumab every 8 weeks is noninferior to eculizumab every 2 weeks across all efficacy end points in C5 inhibitor–naive PNH patients. are employees and stockholders of Alexion Pharmaceuticals, Inc. J.W.L. Like the first-generation C5 inhibitor, eculizumab, ravulizumab … The alternative complement pathway is characterized by the cleavage of the complement protein C5into C5a and C5b fragments. have received honoraria and consulting fees from Alexion Pharmaceuticals, Inc. to those observed in major eculizumab trials; however, fewer patients in the ravulizumab Demographic and baseline clinical characteristics, Erythrocytes with complete deficiency in glycosylphosphatidylinositol-anchored proteins, including complement regulatory proteins CD59 and CD55.30. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. and R.P.d.L. There were no treatment-emergent antidrug antibodies in patients treated with ravulizumab. Ravulizumab every 8 weeks is noninferior to eculizumab every 2 weeks across all efficacy end points in eculizumab-experienced PNH patients. This study demonstrates that patients with PNH may be safely and effectively switched from eculizumab (900 mg administered every 2 weeks) to ravulizumab administered every 8 weeks while maintaining the high level of efficacy, safety, and quality of life previously achieved with eculizumab. With ULTOMIRIS, you can experience the freedom of up to 8 weeks between infusions a, with the comfort of established safety.Whether you or a child you care for had a recent atypical-HUS diagnosis, or you’ve been part of the atypical-HUS … As expected in a patient population that was clinically stable on eculizumab therapy, the proportion of patients who achieved normalization in LDH was relatively stable over time. Qualified academic investigators may request participant-level, de-identified clinical data and supporting documents (statistical analysis plan and protocol) pertaining to this study. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. Further details regarding data availability, instructions for requesting information, and our data disclosure policy are available at the Alexion Web site (http://alexion.com/research-development). If you already have an account, you can login, however profile updates, purchases and subscription activations will be disabled until after the upgrade. By continuing you agree to the Use of Cookies. half-life that is over 4 times greater than that of eculizumab (~ 51.8 days vs. ~ 11 days) and offers a reduced dosing fre-quency of 4–8 weeks vs. every 2–3 weeks, depending on bodyweight [14]. 1 Last year, ravulizumab (Ultomiris), a long-acting C5 inhibitor derived from eculizumab, received FDA and EMEA approval for the treatment of patients with paroxysmal nocturnal hematuria (PNH). The sponsor and investigators thank the patients and their families for their participation in, and support for, this clinical study. No meningococcal infections or discontinuations due to adverse events occurred. a The mean (SD) terminal elimination half-life and clearance of ravulizumab-cwvz in patients with PNH are 49.7 (8.9) days and 0.08 (0.022) L/day, respectively. Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. Although LDH levels increased by 8.4% in the eculizumab group and decreased 0.82% in the ravulizumab group at day 183, the difference did not reach statistical significance for superiority (P = .058). The body’s immune system uses the complement pathway to mark pathogens for targeted destruction by immune cells. Pyrexia and hemolysis were the only serious adverse events reported by >1 patient (3 and 2 patients, respectively, all in the eculizumab group). Ravulizumab (ALXN1210) is a new complement component 5 (C5) inhibitor that produces immediate, complete, and sustained inhibition of C5 with an extended, 8-week dosing interval. The content on this site is intended for healthcare professionals. Post hoc P values were calculated for testing of noninferiority (Pinf) relative to the prespecified noninferiority margins to assess the strength of evidence of the study results. Patient demographics and baseline clinical characteristics were well balanced between treatment groups (Table 1). Patients with PNH may be safely and effectively switched from labeled-dose eculizumab every 2 weeks to ravulizumab every 8 weeks. Ravulizumab for treating atypical haemolytic uraemic syndrome (aHUS) [ID1530] (%), LDH, least squares mean % change (95% CI), Difference in percentage change from baseline, FACIT-Fatigue score, least squares mean change (95% CI), Total number of packed red blood cell units transfused, mean (SD), Patients with major adverse vascular events, n (%), Patients with adverse events leading to withdrawal of study drug, Patients with serious adverse events leading to withdrawal of study drug. Ravulizumab and eculizumab were well tolerated in this study. Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complementpathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) andsevere end-organ damage. The publication costs of this article were defrayed in part by page charge payment. Baseline European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 subscale scores reflected a patient population with stable disease, and changes in scores during the study were similar in both treatment groups (supplemental Appendix, section 4; supplemental Table 1). Blood. Patients were stratified according to transfusion history and were randomly assigned (1:1) to 26 weeks of open-label treatment with IV ravulizumab or eculizumab. [1] Difference (Diff) (95% CI) was based on estimated difference in percentage with 95% CI. Baseline was defined as the last nonmissing value before the first dose of study drug. 14 As previously described, eculizumab binds to the complement protein C5 in the intravascular space. Baseline (BL) is defined as the last nonmissing value before first dose of study drug. Genetic variants in C5 and poor response to eculizumab. Key secondary efficacy end points were proportion of patients with breakthrough hemolysis, defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2× the ULN after prior reduction of LDH to <1.5× the ULN on treatment; change from baseline in quality of life, assessed with the FACIT-Fatigue Scale Version 4.0; transfusion avoidance, defined as the proportion of patients who remained transfusion free and did not require a transfusion per protocol-specified guidelines; and proportion of patients with stabilized hemoglobin, defined as avoidance of a ≥2-g/dL decrease in hemoglobin level from baseline in the absence of transfusion. treatment. Ravulizumab-cwvz (Ultomiris, Alexion) received FDA approval for the treatment of atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA) for adult and pediatric patients. Drug maker Alexion, developer of the rare disease drug eculizumab (Soliris), announced Friday that the FDA has accepted for priority review its long-acting C5 complement inhibitor, ravulizumab (Ultomiris), which offers less frequent administration than eculizumab. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. This 26-week, active-controlled study of 195 patients with PNH who were clinically stable on labeled-dose eculizumab treatment for a mean for 5.8 years demonstrated that ravulizumab administered every 8 weeks effectively inhibited complement-mediated hemolysis and had a safety profile similar to that of eculizumab.5-7  Ravulizumab met the primary end point (percentage change in LDH from baseline to day 183) and all key secondary end points, showing noninferiority to biweekly treatment with 900 mg eculizumab, the current standard of care for PNH.13,14  Point estimates consistently favored ravulizumab treatment over eculizumab treatment for the primary end point and all 4 key secondary efficacy end points, although none of the results from this noninferiority trial demonstrated superiority. Adverse events were recorded by type, incidence, and severity. Antidrug antibodies were also assessed. Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor–naive patients with paroxysmal nocturnal hemoglobinuria (PNH). The life time horizon used in the costs of treatments is not stated, but the relative life time costs are reported at around $9.4m for Eculizumab and $7.8m for Ravulizumab. You will then receive an email that contains a secure link for resetting your password, If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password, DOI: https://doi.org/10.1016/j.kint.2020.03.011. On average, patients had received eculizumab therapy for 5.8 years before study entry. Other secondary efficacy outcomes at day 183. Given that the patients enrolled in this study were stable on eculizumab therapy and LDH levels were within the normal range at baseline, and given the highly efficacious nature of eculizumab, differences between treatments were expected to be minimal.15-17  However, 5 patients receiving eculizumab experienced breakthrough hemolysis, whereas no events of breakthrough hemolysis were observed in patients switched to ravulizumab. A difference in percentage change in LDH from baseline to day 183 between ravulizumab and eculizumab treatment groups along with a 2-sided 95% confidence interval (CI) were calculated. treatment of aHUS. Ravulizumab (ravulizumab-cwvz; ULTOMIRIS™), a humanized monoclonal antibody, is a complement C5 inhibitor developed by Alexion Pharmaceuticals for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS). R.P.d.L. 23 In ravulizumab… PCHG, percentage change. Day 29, 43, 57, 85, 99, 113, 141, 155, and 169 data are from anytime for the ravulizumab group and predose for the eculizumab group. Elsevier journal websites will be undergoing maintenance on Monday March 15 from 3:00 am to 5:00 pm US Eastern. 2019;133(6):530-539. All participants gave written informed consent prior to study participation. … This calculation was made so that all positive estimates of treatment effects indicated a greater effect of ravulizumab, and all negative treatment estimates indicated a greater effect of eculizumab. b Targeted engineering to incorporate 4 amino acid substitutions designed to reduce target-mediated drug disposition and enhance FcRn-mediated recycling into eculizumab … The lower bound of the 95% CI for the difference was −0.42%, which exceeded the protocol-specified noninferiority margin of −15%, indicating that ravulizumab is noninferior to eculizumab with a Pinf < .0006. Of the 195 patients who received treatment, 191 completed the 26-week treatment period (ravulizumab, n = 96; eculizumab, n = 95). In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Contribution: A.G.K., A.H., J.S., and S.N. No patients in the ravulizumab group experienced breakthrough hemolysis compared with 5 (5.1%) patients in the eculizumab group (difference, 5.1% [95% CI, −8.89% to 18.99%, Pinf < .0004). Soliris is also used to treat atypical … Both ravulizumab and eculizumab dramatically improved the platelet count after 1 week. … The online version of this article contains a data supplement. C5a is a pro-in… An overview of adverse events is shown in Table 4. Of these 5 patients with breakthrough hemolysis, 4 had 1 event each and 1 had 3 events, the third of which resulted in hospitalization and subsequent study discontinuation because of lack of efficacy (this patient subsequently received eculizumab 1200 mg every 2 weeks). If at any point noninferiority or superiority was not reached, then all subsequent tests were stopped. Among 7 episodes of breakthrough hemolysis, 4 were associated with inadequate C5 inhibition, 2 were primarily associated with infection, and 1 was of unclear etiology. Atypical and secondary haemolytic uremic syndromes have a distinct presentation and no common genetic risk factors. Additionally, 2 events with complete C5 inhibition were associated with infection. For the primary end point of percentage change in LDH and the secondary end point of breakthrough hemolysis, estimates of the treatment difference were based upon (eculizumab − ravulizumab), while the remainder of the end points were based upon (ravulizumab − eculizumab).
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