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      Long-Term Efficacy and Safety of Hizentra® in Patients with Primary Immunodeficiency in Japan, Europe, and the United States: a Review of 7 Phase 3 Trials

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          Abstract

          Many patients with primary immunodeficiency (PID) require immunoglobulin G (IgG) replacement therapy, delivered as intravenous IgG (IVIG) or subcutaneous IgG (SCIG). We aim to identify trends in efficacy and safety that would not be evident in individual studies of small patient numbers. Seven open-label, Phase 3, prospective, multicenter studies of the efficacy and safety of Hizentra® (a SCIG), conducted in Japan, Europe, and the US were summarized. Overall, 125 unique patients received 15,013 weekly infusions during a total observation period of 250.9 patient-years. Mean weekly doses of Hizentra® were 83.22–221.3 mg/kg body weight; infusion rates per patient (total body rate) were 25.2–49.3 mL/h across studies. The rates of infections and serious bacterial infections were 3.10 and 0.03 events per patient/year, respectively. Annualized rates of days hospitalized due to infection, out of work/school, and prophylactic antibiotic use were 0.95, 5.14, and 36.78 per patient, respectively. For the equivalent monthly dose, weekly Hizentra® SCIG administration resulted in expectedly-increased serum IgG trough levels in patients switching from IVIG, and maintained levels in patients switching from previous SCIG. Adverse events (AEs) totaled 5039 (events/infusion 0.094–0.773), almost all of which were mild/moderate. Three thousand one hundred ninety-seven were considered treatment-related, the most common of which were injection site reactions (2919 events; 0.001–0.592 AEs per infusion). Systemic AEs were very uncommon. The results from these seven studies indicate that Hizentra® therapy was both efficacious and well tolerated during long-term treatment. This is particularly important in patients with PID, who may require lifelong IgG replacement therapy.

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          Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home.

          A large number of children and adults with primary antibody deficiencies need lifelong IgG replacement therapy. It is mostly unknown what effect the choice of replacement therapy has on the patients' health-related quality of life (HRQOL) and treatment satisfaction (TS). To investigate whether a switch from hospital-based intravenous IgG (IVIG) to home-based subcutaneous IgG (SCIG) therapy would improve the HRQOL and TS. Fifteen children ( or =14 years; 22 on hospital-based IVIG and 10 on home-based SCIG therapy at enrollment) were included. Questionnaires were completed at baseline and at 6 and 10 months: the Child Health Questionnaire-Parental Form 50 (children) or Short Form 36 (adults), the Life Quality Index, and questions regarding therapy preferences. The SCIG home therapy was reported to give better health (P=.001) and improved school/social functioning (P=.02) for the children, reduced emotional distress (P=.02) and limitations on personal time for the parents (P=.004), and fewer limitations on family activities (P=.002). Adults switching therapy reported improved vitality (P=.04), mental health ( P=.05), and social functioning ( P=.01). Adults already on SCIG home therapy at enrollment retained high HRQOL and TS scores. The SCIG home therapy improved TS because it led to greater independence and better therapy convenience ( P <.05). The patients preferred the SCIG administration route and having the treatment at home. Home-based SCIG therapy improves several important aspects of HRQOL and provides the patients with primary antibody deficiencies and their families with greater independence and better control of the therapy situation and daily life. SCIG home therapy is an appreciated therapeutic alternative for adults and children in need of lifelong IgG replacement therapy.
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            Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases.

            Intravenous immunoglobulin (IVIg) infusions at 3-4 week intervals are currently standard therapy in the United States for patients with primary immune deficiency diseases (PIDD). To evaluate alternative modes of immunoglobulin administration we have designed an open-label study to investigate the efficacy and safety of a subcutaneously administered immunoglobulin preparation (16% IgG) in patients with PIDD. After their final IVIg infusion, 65 patients entered a 3-month, wash-in/wash-out phase, designed to bring patients to steady-state with subcutaneously administered immunoglobulin. This was followed by 12 months of weekly SCIg infusions, at a dose determined in a pharmacokinetic substudy to provide noninferior intravascular exposure. This resulted in a mean weekly dose of 158 mg/kg, calculated to equal 137% of the previous intravenous dose. Two patients (4%) each reported 1 serious bacterial infection (pneumonia), an annual rate of 0.04 per patient-year. There were 4.43 infections of any type per patient-year. Mean trough serum IgG levels increased from 786 to 1040 mg/dL during the study, a mean increase of 39%. The most frequent treatment-related adverse event was infusion-site reaction, reported by 91% of patients; this was predominantly mild or moderate, and the incidence decreased over time. No treatment-related serious adverse events were reported. We conclude that subcutaneous administration of 16% SCIg is a safe and effective alternative to IVIg for replacement therapy of PIDD.
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              Current treatment options with immunoglobulin G for the individualization of care in patients with primary immunodeficiency disease.

              Primary antibody deficiencies require lifelong replacement therapy with immunoglobulin (Ig)G to reduce the incidence and severity of infections. Both subcutaneous and intravenous routes of administering IgG can be effective and well tolerated. Treatment regimens can be individualized to provide optimal medical and quality-of-life outcomes in infants, children, adults and elderly people. Frequency, dose, route of administration, home or infusion-centre administration, and the use of self- or health-professional-administered infusion can be tailored to suit individual patient needs and circumstances. Patient education is needed to understand the disease and the importance of continuous therapy. Both the subcutaneous and intravenous routes have advantages and disadvantages, which should be considered in selecting each patient's treatment regimen. The subcutaneous route is attractive to many patients because of a reduced incidence of systemic adverse events, flexibility in scheduling and its comparative ease of administration, at home or in a clinic. Self-infusion regimens, however, require independence and self-reliance, good compliance on the part of the patient/parent and the confidence of the physician and the nurse. Intravenous administration in a clinic setting may be more appropriate in patients with reduced manual dexterity, reluctance to self-administer or a lack of self-reliance, and intravenous administration at home for those with good venous access who prefer less frequent treatments. Both therapy approaches have been demonstrated to provide protection from infections and improve health-related quality of life. Data supporting current options in IgG replacement are presented, and considerations in choosing between the two routes of therapy are discussed.
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                Author and article information

                Contributors
                +44 29 2074 5814 , JollesSR@cardiff.ac.uk
                Journal
                J Clin Immunol
                J. Clin. Immunol
                Journal of Clinical Immunology
                Springer US (New York )
                0271-9142
                1573-2592
                10 November 2018
                10 November 2018
                2018
                : 38
                : 8
                : 864-875
                Affiliations
                [1 ]ISNI 0000 0001 0169 7725, GRID grid.241103.5, Immunodeficiency Centre for Wales, , University Hospital of Wales, ; Cardiff, UK
                [2 ]ISNI 0000 0004 0524 3511, GRID grid.428413.8, CSL Behring LLC, ; King of Prussia, PA USA
                [3 ]ISNI 0000 0004 0625 2858, GRID grid.420252.3, CSL Behring GmbH, ; Marburg, Germany
                [4 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, School of Medicine and the Melvin and Bren Simon Cancer Center, , Indiana University, ; Indianapolis, IN USA
                [5 ]GRID grid.414873.d, Medical City Children’s Hospital, ; Dallas, TX USA
                [6 ]ISNI 0000 0001 2230 9752, GRID grid.9647.c, Hospital St. Georg GmbH Leipzig, , Academic Teaching Hospital of the University of Leipzig, ; Leipzig, Germany
                [7 ]ISNI 0000 0001 1014 9130, GRID grid.265073.5, Department of Community Pediatrics, Perinatal and Maternal Medicine, , Tokyo Medical and Dental University (TMDU), ; Tokyo, Japan
                [8 ]ISNI 0000 0001 1014 9130, GRID grid.265073.5, Department of Child Health and Development, Graduate School of Medical and Dental Sciences, , Tokyo Medical and Dental University (TMDU), ; Tokyo, Japan
                Author information
                http://orcid.org/0000-0002-7394-6804
                Article
                560
                10.1007/s10875-018-0560-5
                6292970
                30415311
                e46d1ff4-2935-4119-b7f1-4f422b1f2215
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 6 April 2018
                : 4 October 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100008322, CSL Behring;
                Categories
                Original Article
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2018

                Immunology
                immunoglobulin g replacement therapy,primary antibody deficiencies,primary immunodeficiencies,ivig,scig

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