A randomized controlled pilot trial of anakinra for hemodialysis inflammation

Abstract

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients. Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients. The mortality rate for patients undergoing maintenance hemodialysis is unacceptably high with most of the deaths due to cardiovascular disease, infection, or protein-energy wasting.1Himmelfarb J. Ikizler T.A. Hemodialysis. N Engl J Med. 2010; 363: 1833-1845Crossref PubMed Scopus (253) Google Scholar Randomized controlled trials targeting traditional and nontraditional cardiovascular risk factors have had a minimal impact on survival in this population. Inflammatory biomarkers are predictors of cardiovascular events and mortality in the hemodialysis population,2Kimmel P.L. Phillips T.M. Simmens S.J. et al.Immunologic function and survival in hemodialysis patients.Kidney Int. 1998; 54: 236-244Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar, 3Stenvinkel P. Barany P. Heimburger O. et al.Mortality, malnutrition, and atherosclerosis in ESRD: what is the role of interleukin-6?.Kidney Int Suppl. 2002; : 103-108Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 4Stenvinkel P. Heimburger O. Jogestrand T. Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity.Am J Kidney Dis. 2002; 39: 274-282Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar and inflammation has been implicated in the pathogenesis of atherosclerosis and protein-energy wasting.5Ross R. Atherosclerosis—an inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (19530) Google Scholar, 6Ikizler T.A. Nutrition, inflammation and chronic kidney disease.Curr Opin Nephrol Hypertens. 2008; 17: 162-167Crossref PubMed Scopus (57) Google Scholar, 7Amdur R.L. Feldman H.I. Dominic E.A. et al.Use of measures of inflammation and kidney function for prediction of atherosclerotic vascular disease events and death in patients with CKD: findings from the CRIC study.Am J Kidney Dis. 2019; 73: 344-353Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 8Ikizler T.A. Burrowes J.D. Byham-Gray L.D. et al.KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update.Am J Kidney Dis. 2020; 76: S1-S107Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar Suppressing inflammation with anticytokine therapy has been proposed to reduce inflammation-associated morbidity, but there are few studies using this strategy for patients receiving maintenance hemodialysis. High levels of interleukin-1β (IL-1β), a highly active proinflammatory cytokine, and its naturally occurring receptor antagonist (IL-1ra) have been well documented in kidney failure.2Kimmel P.L. Phillips T.M. Simmens S.J. et al.Immunologic function and survival in hemodialysis patients.Kidney Int. 1998; 54: 236-244Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar,9Descamps-Latscha B. Herbelin A. Nguyen A.T. et al.Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis. Relationships with activation markers of T cells, B cells, and monocytes.J Immunol. 1995; 154: 882-892Crossref PubMed Google Scholar,10Pereira B.J. Shapiro L. King A.J. et al.Plasma levels of IL-1 beta, TNF alpha and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients.Kidney Int. 1994; 45: 890-896Abstract Full Text PDF PubMed Scopus (363) Google Scholar Treatment with IL-1ra is an established approach for rheumatoid arthritis, autoinflammatory conditions, and gout,11Bresnihan B. Alvaro-Gracia J.M. Cobby M. et al.Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist.Arthritis Rheum. 1998; 41: 2196-2204Crossref PubMed Scopus (941) Google Scholar, 12Hoffman H.M. Rosengren S. Boyle D.L. et al.Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist.Lancet. 2004; 364: 1779-1785Abstract Full Text Full Text PDF PubMed Scopus (483) Google Scholar, 13Hawkins P.N. Lachmann H.J. McDermott M.F. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome.N Engl J Med. 2003; 348: 2583-2584Crossref PubMed Scopus (402) Google Scholar, 14Saag K.G. Khanna P.P. Keenan R.T. et al.A randomized, phase II study evaluating the efficacy and safety of anakinra in the treatment of gout flares.Arthritis Rheumatol. 2021; 73: 1533-1542Crossref PubMed Scopus (25) Google Scholar but neither the safety nor efficacy of targeting IL-1 for chronic inflammation in the setting of hemodialysis has been established. We performed a pilot, double-blind, randomized, placebo-controlled trial to evaluate the safety and tolerability of anakinra, an IL-1ra, for patients receiving maintenance hemodialysis, and to explore its efficacy on biochemical and patient-reported outcomes. An important goal of this early phase study was to assess the feasibility of a subsequent trial powered to assess efficacy on clinical outcomes. ACTION was a parallel group, double-blind, randomized, placebo-controlled pilot trial to evaluate safety, tolerability, and feasibility, and explore the efficacy of anakinra among hemodialysis patients (NCT03141983). The full protocol is available in the Supplementary Materials. Participants were enrolled from dialysis units affiliated with Brigham and Women’s Hospital, Boston, Massachusetts; George Washington University, Washington, DC; University of Washington, Seattle, Washington; and Vanderbilt University Medical Center, Nashville, Tennessee. An external Data and Safety Monitoring Board, appointed by the National Institute of Diabetes and Digestive and Kidney Diseases, approved the protocol and reviewed progress, quality, and safety during trial conduct. The institutional review boards affiliated with the enrolling centers and with the Data Coordinating Center (University of Pennsylvania) approved the protocol. All participants provided written informed consent. The inclusion criteria included age 18–85 years, treatment with hemodialysis for ≥6 months, and negative testing for human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis C antibody or documented hepatitis C viral clearance following direct antiviral therapy, and tuberculosis using an interferon gamma release assay. 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The that anakinra be to patients on maintenance hemodialysis. and were not The patients receiving anakinra a 41% decrease in C-reactive protein levels with a 6% decrease in the placebo but this was not statistically significant. PDF

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