BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, not malignant, disease of the hematopoietic stem cells, associated with significant morbidity and mortality. It is a rare disease with an estimated incidence of 1.3 new cases per one million individuals per year. The treatment of PNH has been largely empirical and symptomatic, with blood transfusions, anticoagulation, and supplementation with folic acid or iron. Eculizumab, a biological agent that inhibits complement cascade, was developed for preventing hemolytic anemia and severe thrombotic episodes. OBJECTIVES: To assess the clinical benefits and harms of eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria (PNH). SEARCH METHODS: We conducted a comprehensive search strategy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2014, Issue 5), Ovid MEDLINE (from 1946 to 15 May 2014), EMBASE (from 1980 to 25 June 2014), and LILACS (from 1982 to 25 June 2014). We did not apply any language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) irrespective of their publication status or language. No limits were applied with respect to period of follow-up. We excluded quasi-RCTs. We included trials comparing eculizumab with placebo or best available therapy. We included any patient with a confirmed diagnosis of PNH. Primary outcome was overall survival. DATA COLLECTION AND ANALYSIS: We independently performed a duplicate selection of eligible trials, risk of bias assessment, and data extraction. We estimated risk ratios (RRs) and 95% confidence interval (CIs) for dichotomous outcomes, and mean differences (MDs) and 95% CIs for continuous outcomes. We used a random-effects model for analysis. MAIN RESULTS: We identified one multicenter (34 sites) phase III RCT involving 87 participants. The trial compared eculizumab versus placebo, and was conducted in the US, Canada, Europe, and Australia with 26 weeks of follow-up. This small trial had high risk of bias in many domains (attrition and selective reporting). It was sponsored by a pharmaceutical company. No patients died during the study. By using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (scores can range from 0 to 100, with higher scores on the global health status and functioning scales indicating improvement), the trial showed improvement in health-related quality of life in patients treated with eculizumab (mean difference (MD) 19.4, 95% CI 8.25 to 30.55; P = 0.0007; low quality of evidence). By using the Functional Assessment of Chronic Illness Therapy Fatigue instrument (scores can range from 0 to 52, with higher scores indicating improvement in fatigue), the trial showed a reduction in fatigue (MD 10.4, 95% CI 9.97 to 10.83; P = 0.00001; moderate quality of evidence) in the eculizumab group compared with placebo. Eculizumab compared with placebo showed a greater proportion of patients with transfusion independence: 51% (22/43) versus 0% (0/44); risk ratio (RR) 46.02, 95% CI 2.88 to 735.53; P = 0.007; moderate quality of evidence; and withdrawal for any reason: 4.7% (2/43) versus 22.72% (10/44); RR 0.20, 95% CI 0.05 to 0.88; P = 0.03; moderate quality of evidence. Due to the low rate of events observed, the included trial did not show any difference between eculizumab and placebo in terms of serious adverse events: 9.3% (4/43) versus 20.4% (9/44); RR 0.15, 95% CI 0.15 to 1.37; P = 0.16; low quality of evidence. We did not observe any difference between intervention and placebo for the most frequent adverse events. One participant receiving placebo showed an episode of thrombosis. The trial did not assess overall survival, transformation to myelodysplastic syndrome and acute myelogenous leukemia, or development or recurrence of aplastic anemia on treatment. AUTHORS' CONCLUSIONS: This review has detected an absence of evidence for eculizumab compared with placebo for treating paroxysmal nocturnal hemoglobinuria (PNH), in terms of overall survival, nonfatal thrombotic events, transformation to myelodysplastic syndrome and acute myelogenous leukemia, and development and recurrence of aplastic anemia on treatment. Current evidence indicates that compared with placebo, eculizumab increases health-related quality of life and increases transfusion independence. During the execution of the included trial, no patients died. Furthermore, the intervention seems to reduce fatigue and withdrawals for any reason. The safety profile of eculizumab is unclear. These conclusions are based on one small trial with risk of attrition and selective reporting bias.Therefore, prescription of eculizumab for treating patients with PNH can neither be supported nor rejected, unless new evidence from a large high quality trial alters this conclusion. Therefore, we urge the reader to interpret the trial results with much caution. Future trials on this issue should be conducted according to the SPIRIT statement and reported according to the CONSORT statement by independent investigators, and using the Foundation of Patient-Centered Outcomes Research recommendations.

RECORD STATUS: None CITATION: Pichon Riviere A, Augustovski F, Garcia Marti S, Alcaraz A, Glujovsky D, Lopez A, Rey-Ares L, Bardach A, Regueiro A. Efectividad del eculizumab para el tratamiento de la hemoglobinuria paroxistica nocturna. [Effectiveness of eculizumab in the treatment of paroxysmal nocturnal hemoglobinuria] Buenos Aires: Institute for Clinical Effectiveness and Health Policy (IECS). Informe de Respuesta Rapida No 219. 2011

INTRODUCCIÓN; A la fecha, no está aprobado el uso de vacunas o tratamientos farmacológicos convencionales para el tratamiento de COVID-19. No obstante, algunos especialistas vienen recomendando el uso de tratamientos alternativos para prolongar la vida de los pacientes infectados lo suficiente hasta que el cuerpo responda a la terapia de soporte (Hudson Medical 2020). Esto, considerando la experiencia previa de la epidemia del SARS-CoV, en la cual se evidenció que la activación sistemática de los componentes del complemento en los pulmones conllevaba una respuesta inflamatoria descontrolada, con la consiguiente producción de una serie de citoquinas y quimioquinas que gatillaban una mayor inflamación y reclutamiento de neutrófilos. Así, se tuvo un particular interés por los componentes del complemento conocidos como anafilatoxinas, las cuales son las formas activadas del complemento C3, C4 y C5 (i. e. C3a, C4a, y C5a, respectivamente), las cuales tendrían una de las propiedades proinflamatorias más potentes del sistema del complemento (Gralinski et al. 2018). En ese sentido, se ha propuesto el bloqueo del C5a como un tratamiento para la injuria pulmonar aguda durante la patogénesis de algunas infecciones virales (Wang et al. 2015), sustentado en el hecho de que el uso de anticuerpos contra el C5a habría mostrado tener un efecto protector durante la infección del virus de la influenza H5N1 en ratones (Sun et al. 2013). Teniendo en cuenta lo antes mencionado, se ha propuesto el uso de eculizumab (SolirisÒ), un anticuerpo monoclonal con alta afinidad por la proteína C5 del complemento, cuya unión inhibe su activación a C5a y que ha sido aprobado por la FDA para hemoglobinuria paroxística nocturna, síndrome urémico hemolítico atípico, y miastenia gravis generalizada (FDA 2019). Algunos especialistas han propuesto la hipótesis de que eculizumab reduciría la inflamación sistémica y el daño pulmonar grave, lo cual mejoraría la probabilidad de supervivencia de los pacientes con distrés respiratorio agudo causado por la infección del SARS-CoV-2 (COVID-19)(AEMPS 2020; Hudson Medical 2020). MÉTODOS: Se llevó a cabo una búsqueda bibliográfica sistemática rápida de la literatura con respecto a la eficacia y seguridad de eculizumab para el tratamiento de pacientes adultos con COVID 19. Para ello realizó tanto una búsqueda sistemática en las principales bases de datos, tales como MEDLINE vía PubMed y en Cochrane Library. Así mismo, se realizó una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud, así en las principales sociedades o instituciones especializadas, tales como la World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), y The National Institute for Health and Care Excellence (NICE). Adicionalmente, se buscaron ensayos clínicos en desarrollo o que no hayan sido publicados aún en la página web www.clinicaltrials.gov y http://apps.who.int/trialsearch que contengan estudios acerca de eculizumab y así disminuir el sesgo de publicación. Finalmente, se consideró extraer información con una estrategia de "bola de nieve" mediante la revisión de las listas de referencias de las revisiones sistemáticas, estudios primarios y revisiones narrativas seleccionadas que sean de relevancia. RESULTADOS: Guías de práctica clínica (GPC). Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID19). Updated March 7, 2020 (CDC 2020). La GPC de la CDC, actualizada el 20 de marzo del 20201 , indica que no está disponible ningún tratamiento específico para el COVID-19. La GPC de la CDC no hace ninguna recomendación específica respecto al uso de eculizumab en los pacientes con COVID-19. World Health Organization (WHO). Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected. Interim guidance (WHO 2020). La GPC. interina de la OMS está destinada a los médicos que atienden a niños y adultos infectados con SARS-CoV-2, publicada el 13 de marzo del 2020 (WHO/2019-nCoV/clinical/2020.4)2 . La GPC de la OMS no hace ninguna recomendación específica respecto al uso de eculizumab en los pacientes con COVID-19. Agrega que existen una gran cantidad de ensayos clínicos que se están llevando a cabo respecto a la eficacia y seguridad de algunos antivirales y que están registrados en las páginas web clinicaltrials.gov y http://www.chictr.org.cn/abouten.aspx The National Institute for Health and Care Excellence (NICE). Coronavirus (COVID19). Rapid guidelines and evidence reviews (NICE 2020). NICE ha publicado una serie de GPC3 que cubren el manejo de los pacientes críticos, pacientes en diálisis y de pacientes con tratamientos antineoplásicos, que se encuentran con COVID-19. A la fecha, no ha realizado ninguna recomendación específica respecto al uso de eculizumab en los pacientes con COVID-19. Ensayos clínicos aleatorizados (ECA) de eculizumab en COVID-19. No se encontraron ECA que hayan evaluado el uso de eculizumab en pacientes con COVID-19. Ensayos clínicos aleatorizados (ECA) de eculizumab en COVID-19. No se encontraron ECA que hayan evaluado el uso de eculizumab en pacientes con COVID-19. Casos clínicos de eculizumab en COVID-19. No se encontraron casos clínicos publicados que hayan reportado el uso de eculizumab en pacientes con COVID-19. Estudios en progreso o no publicados. Eculizumab (Soliris) in Covid-19 Infected Patients (SOLID-C19). Dicho estudio es un ensayo clínico de fase 1, de etiqueta abierta, que estará a cargo del Dr. Thomas Pitts del Hudson Medical y tiene como objetivo evaluar la seguridad y la eficacia preliminar de eculizumab + tratamiento estándar en pacientes adultos con COVID-19, de la manera más precoz posible. Se excluirá a los pacientes intubados. No cuenta con fecha prevista de culminación del estudio. CONCLUSIÓN: No se han encontrado estudios que proporcionen evidencia científica a la fecha sobre el uso de eculizumab en pacientes con COVID-19. La propuesta del uso de eculizumab en COVID-19 se basa meramente en una plausibilidad biológica hipotetizada de acuerdo con la fisiopatología de la injuria pulmonar aguda causada por las infecciones virales, no específicamente para COVID-19. Las GPC disponibles a la fecha no mencionan el uso de eculizumab para el tratamiento de COVID-19. Por lo tanto, a la fecha no es posible sustentar técnicamente una recomendación a favor de uso eculizumab en el tratamiento de pacientes COVID-19.

RECORD STATUS: This is a bibliographic record of an ongoing health technology assessment being undertaken by a member of INAHTA. Links to the published report and any other relevant documentation will be added when available. CITATION: Eculizumab for atypical haemolytic uraemic syndrome. Barcelona: Catalan Agency for Health Information, Assessment and Quality (CAHIAQ -formerly CAHTA).

OBJECTIVE: To determine the efficacy and safety of eculizumab for patients with atypical haemolytic uraemic syndrome (aHUS), compared with current treatment options. DESIGN: A systematic review was performed according to the general principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All study designs were included, except case histories. PARTICIPANTS: All patients diagnosed with aHUS were included; no age restrictions were used. INTERVENTIONS: Eculizumab compared with current treatment options. IDENTIFICATION OF STUDIES: 12 databases were searched. Additional searches were performed through the Food and Drug Administration (FDA) and the Electronic Medicines Compendium websites, Google internet searches and contacting clinical experts. Reference lists of relevant articles were checked for additional studies. RESULTS: 2 small, uncontrolled prospective multinational, multicentre studies and one small uncontrolled multinational, multicentre retrospective study were included. No meta-analyses were performed. Compared with baseline measures, thrombotic microangiopathy event-free status was achieved in 84% of patients in the prospective studies. Adverse events, as documented by enrolling investigators were frequent, with upper-respiratory tract infection affecting a third of patients. No deaths or episodes of meningitis or meningococcal septicaemia occurred in the prospective studies. Results of the study extension phases up to 114 weeks indicate that the benefits of the treatment are sustained. CONCLUSIONS: Eculizumab is clinically effective for the treatment of aHUS. Further research is needed to evaluate eculizumab, ideally using patient-related clinical outcomes. If randomised studies are not feasible, study investigators should ensure that the threat of bias is minimised in future studies of eculizumab with respect to the reporting of patient recruitment and selection.

BACKGROUND: We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed. RESULTS: Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae. CONCLUSIONS: Eculizumab is an effective therapy for PNH.

RECORD STATUS: This is a bibliographic record of an ongoing health technology assessment being undertaken by a member of INAHTA. Links to the published report and any other relevant documentation will be added when available. CITATION: Eculizumab for treating atypical haemolytic uraemic syndrome. Health Technology Assessment

In this study, we aimed to systematically review available literature on the efficacy of eculizumab for the treatment of renal involvement in patients with systemic lupus erythematosus (SLE). We conducted a literature search developed a priori, to identify articles reporting clinical experience with the use of eculizumab in SLE patients, focusing on renal involvement. The search strategy was applied to Ovid MEDLINE, EMBASE, In-Process and Other Non-Indexed Citation, Cochrane Central Register of Controlled Trials and Scopus from 2006 to present. Abstracts from EULAR and ACR congresses were also screened. We included six publications describing the renal outcome in SLE patients receiving eculizumab. Five out of six cases described the occurrence of thrombotic microangiopathy (TMA) in renal biopsies of patients with known SLE; three cases with biopsy-proven lupus nephritis (LN) and two patients with SLE-related antiphospholipid syndrome without histologic evidence of LN. One study reported the outcome of a patient with severe refractory LN successfully treated with eculizumab. All patients, regardless of the presence of concomitant LN, presented with severe hypocomplementemia and renal function impairment. All patients showed a sustained improvement of renal function and normalization of complement parameters after treatment with eculizumab[median follow-up 9 months (1-17)]. Despite the limitations of the currently available evidence, existing data are promising and provide preliminary support for the use of eculizumab in selected cases of SLE with renal involvement, especially in the presence of TMA, or in patients with refractory LN.

RECORD STATUS: This is a bibliographic record of a published health technology assessment. No evaluation of the quality of this assessment has been made for the HTA database. CITATION: All Wales Medicines Strategy Group (AWMSG). Eculizumab (Soliris®) for the treatment of paroxysmal nocturnal haemoglobinuria Penarth: All Wales Therapeutics and Toxicology Centre (AWTTC), secretariat of the All Wales Medicines Strategy Group (AWMSG). AWMSG Secretariat Assessment Report Advice No. 0509. 2009

Hemolysis and hemoglobinemia contribute to serious clinical sequelae in hemolytic disorders. In paroxysmal nocturnal hemoglobinuria (PNH) patients, hemolysis can contribute to thromboembolism (TE), the most feared complication in PNH, and the leading cause of disease-related deaths. We evaluated whether long-term treatment with the complement inhibitor eculizumab reduces the rate of TE in patients with PNH. Clinical trial participants included all patients in the 3 eculizumab PNH clinical studies, which recruited patients between 2002 and 2005 (n = 195); patients from these studies continued treatment in the current multinational open-label extension study. Thromboembolism rate with eculizumab treatment was compared with the pretreatment rate in the same patients. The TE event rate with eculizumab treatment was 1.07 events/100 patient-years compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 TE events/100 patient-years). With equalization of the duration of exposure before and during treatment for each patient, TE events were reduced from 39 events before eculizumab to 3 events during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n = 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317).