The Inhibition of Complement System in Formal and Emerging Indications: Results from Parallel One-Stage Pairwise and Network Meta-Analyses of Clinical Trials and Real-Life Data Studies

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Abstract

This manuscript presents quantitative findings on the actual effectiveness of terminal complement component 5 (C5) inhibitors and complement component 1 (C1) esterase inhibitors through their formal and common “off-label” (compassionate) indications. The results emanated from pairwise and network meta-analyses to present evidence until September 2019. Clinical trials (CT) and real-life non-randomized studies of the effects of interventions (NRSI) are consistent on the benefits of C5 inhibitors and of the absence of effects of C1 esterase inhibitors ( n = 7484): Mathematically, eculizumab (surface under the cumulative ranking area (SUCRA) >0.6) and ravulizumab (SUCRA ≥ 0.7) were similar in terms of their protective effect on hemolysis in paroxysmal nocturnal hemoglobinuria (PNH), thrombotic microangiopathy (TMA) in atypical hemolytic uremic syndrome (aHUS), and acute kidney injury (AKI) in aHUS, in comparison to pre-/off-treatment state and/or placebo (SUCRA < 0.01), and eculizumab was efficacious on thrombotic events in PNH (odds ratio (OR)/95% confidence interval (95% CI) in CT and real-life NRSI, 0.07/0.03 to 0.19, 0.24/0.17 to 0.33) and chronic kidney disease (CKD) occurrence/progression in PNH (0.31/0.10 to 0.97, 0.66/0.44 to 0.98). In addition, meta-analysis on clinical trials shows that eculizumab mitigates a refractory generalized myasthenia gravis (rgMG) crisis (0.29/0.13 to 0.61) and prevents new acute antibody-mediated rejection (AMR) episodes in kidney transplant recipients (0.25/0.13 to 0.49). The update of findings from this meta-analysis will be useful to promote a better use of complement inhibitors, and to achieve personalization of treatments with this class of drugs.

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Complement: a key system for immune surveillance and homeostasis.

Daniel Ricklin, George Hajishengallis, Kun Lin Yang … (2010)

Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.

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Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

C M Legendre, C licht, P. Muus … (2013)

Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

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Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature.

J. A. Sterne, D Gavaghan, M. Egger (2000)

Publication and selection biases in meta-analysis are more likely to affect small studies, which also tend to be of lower methodological quality. This may lead to "small-study effects," where the smaller studies in a meta-analysis show larger treatment effects. Small-study effects may also arise because of between-trial heterogeneity. Statistical tests for small-study effects have been proposed, but their validity has been questioned. A set of typical meta-analyses containing 5, 10, 20, and 30 trials was defined based on the characteristics of 78 published meta-analyses identified in a hand search of eight journals from 1993 to 1997. Simulations were performed to assess the power of a weighted regression method and a rank correlation test in the presence of no bias, moderate bias or severe bias. We based evidence of small-study effects on P < 0.1. The power to detect bias increased with increasing numbers of trials. The rank correlation test was less powerful than the regression method. For example, assuming a control group event rate of 20% and no treatment effect, moderate bias was detected with the regression test in 13.7%, 23.5%, 40.1% and 51.6% of meta-analyses with 5, 10, 20 and 30 trials. The corresponding figures for the correlation test were 8.5%, 14.7%, 20.4% and 26.0%, respectively. Severe bias was detected with the regression method in 23.5%, 56.1%, 88.3% and 95.9% of meta-analyses with 5, 10, 20 and 30 trials, as compared to 11.9%, 31.1%, 45.3% and 65.4% with the correlation test. Similar results were obtained in simulations incorporating moderate treatment effects. However the regression method gave false-positive rates which were too high in some situations (large treatment effects, or few events per trial, or all trials of similar sizes). Using the regression method, evidence of small-study effects was present in 21 (26.9%) of the 78 published meta-analyses. Tests for small-study effects should routinely be performed in meta-analysis. Their power is however limited, particularly for moderate amounts of bias or meta-analyses based on a small number of small studies. When evidence of small-study effects is found, careful consideration should be given to possible explanations for these in the reporting of the meta-analysis.

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Journal

Journal ID (nlm-ta): Biomedicines

Journal ID (iso-abbrev): Biomedicines

Journal ID (publisher-id): biomedicines

Title: Biomedicines

Publisher: MDPI

ISSN (Electronic): 2227-9059

Publication date (Electronic): 16 September 2020

Publication date Collection: September 2020

Volume: 8

Issue: 9

Electronic Location Identifier: 355

Affiliations

[1 ]Pharmacological Big Data Laboratory, University of Valladolid, 47005 Valladolid, Spain; coralber@ 123456gmail.com (C.B.-G.); alvarez@ 123456med.uva.es (F.J.Á.); de_paz@ 123456med.uva.es (F.J.d.P.); flizarasos@ 123456usmp.pe (F.L.-S.)

[2 ]Pediatric Nephrology Unit, Lausanne University Hospital and University of Lausanne, 1100 Lausanne, Switzerland; hassib.chehade@ 123456chuv.ch (H.C.); Francois.Cachat@ 123456chuv.ch (F.C.)

[3 ]Transplantation Center, Lausanne University Hospital and University of Lausanne, 1100 Lausanne, Switzerland; yannick.muller@ 123456unige.ch (Y.D.M.); julien.vionnet@ 123456kcl.ac.uk (J.V.); Gabriella.Guzzo@ 123456chuv.ch (G.G.); Manuel.Pascual@ 123456chuv.ch (M.P.)

[4 ]King’s College London, London WC2R 2LS, UK

[5 ]Clinical Epidemiology Support Office, Sanidad de Castilla y León, 49022 Zamora, Spain; cochoas2@ 123456gmail.com

[6 ]Ethics Committee of Drug Research–east Valladolid area, University Clinical Hospital of Valladolid, 47005 Valladolid, Spain

[7 ]Department of Nephrology, Hôpital du Valais, 1950 Sion, Switzerland; daniel.teta@ 123456hopitalvs.ch

[8 ]Clinical Nephrology Unit, University Clinical Hospital of Valladolid, 47003 Valladolid, Spain; deboramarg@ 123456yahoo.es

[9 ]Center for Medical Oncology & Hematology, Hospital Thun, 3600 Thun, Switzerland; marcel.adler@ 123456spitalstsag.ch

[10 ]Centro de Investigación en Salud Pública, Instituto de Investigación de la Facultad de Medicina Humana, Universidad de San Martín de Porres, Lima 15024, Peru

[11 ]Department of Nephrology, Hospital Virgen de la Concha, 49022 Zamora, Spain

[12 ]Castile and León’s Research Consolidated Unit n° 299, 47011 Valladolid, Spain

Author notes

[* ]Correspondence: fherrerag@ 123456saludcastillayleon.es ; Tel.: +34-983-423077

[†]

C.B.-G., H.C., Y.D.M., and J.V. are co-first authors.

[‡]

F.H.-G. and M.P. are co-senior authors.

Author information

Coralina Bernuy-Guevara https://orcid.org/0000-0002-5055-3493

Julien Vionnet https://orcid.org/0000-0002-1654-0488

Carlos Ochoa-Sangrador https://orcid.org/0000-0002-7670-3699

F. Javier Álvarez https://orcid.org/0000-0002-7566-5678

Marcel Adler https://orcid.org/0000-0001-7176-2115

Frank Lizaraso-Soto https://orcid.org/0000-0001-9993-9998

Francisco Herrera-Gómez https://orcid.org/0000-0002-3110-692X

Article

Publisher ID: biomedicines-08-00355

DOI: 10.3390/biomedicines8090355

PMC ID: 7554929

PubMed ID: 32948059

SO-VID: fe1762e6-c315-43c8-a9f5-570ac641f97d

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 22 July 2020

Date accepted : 13 September 2020

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The Inhibition of Complement System in Formal and Emerging Indications: Results from Parallel One-Stage Pairwise and Network Meta-Analyses of Clinical Trials and Real-Life Data Studies

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Most cited references 88

Complement: a key system for immune surveillance and homeostasis.

Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature.

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