Subcutaneous Immunoglobulin Replacement Therapy with Hizentra? is Safe and Effective in Two Infants

Hizentra? is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age. We report two infants less than 2 years in which administration of Hizentra? was safe and effective.     

Efficacy and Safety of Subcutaneous Vivaglobin® Replacement Therapy in Previously Untreated Patients with Primary Immunodeficiency: A Prospective,Multicenter Study

Treatment of primary immunodeficiency (PI) is typically initiated with intravenous immunoglobulin (IVIG) loading and then continued with IVIG or subcutaneous IgG (SCIG). This prospective, open-label, multicenter, 6-month study evaluated a new regimen of initiating IgG therapy with SCIG in 18 previously untreated patients. In the loading phase, SCIG 100 mg/kg was administered for five consecutive days (total loading dose 500 mg/kg). During the maintenance phase, patients self-infused SCIG 100 mg/kg/week at home. The primary efficacy endpoint of IgG levels ≥5 g/L on day 12 was achieved in 17 patients (94.4%; 95% CI 0.727, 0.999). The rate of infections was 3.95 episodes/patient/year. Improvement was found in many subscales of the health-related quality of life questionnaires. SCIG treatment was well tolerated, with no related serious adverse events (AEs). Nine (50%) patients experienced related AEs, including local reactions (rate 0.105 events/infusion). The results suggest that therapy of newly diagnosed patients with PI can be initiated directly with SCIG.     

Treatment Satisfaction with Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency: a Pooled Analysis of Six Hizentra® Studies

Purpose

Primary immunodeficiency diseases (PIDDs) are a heterogenous group of disorders characterized by intrinsic impairment in the immune system. Most patients with PIDD require life-long immunoglobulin G replacement therapy, which has been shown to reduce the rate of infections and, related hospitalizations and reduce health-related quality of life (HRQOL). Here, treatment satisfaction and HRQOL in patients with PIDD was evaluated upon switching from intravenous (IVIG) or subcutaneous immunoglobulins (SCIGs) to 20% SCIG (Hizentra®), and during long-term steady-state Hizentra® treatment.

Methods

Analyses were based on two pivotal (switch) and four extension/follow-up (maintenance) Phase III studies of Hizentra® conducted in Europe (EU), Japan (JP), and the United States (US). Two validated questionnaires were used: Life Quality Index (LQI) for assessment of IgG-specific perceptions of HRQOL and Short Form 36 version 2 (SF-36v2).

Results

In the EU and JP switch studies, there was significant and meaningful improvement from Screening in LQI domain scores at all time points, largely driven by patients switching from IVIG to SCIG. In the EU switch study, there were also significant increases in mean SF-36v2 domain scores for Physical Function and General Health from Screening to Week 12. These improvements were observed also at Week 24. Overall, LQI and SF-36v2 domain scores were generally sustained in the maintenance studies.

Conclusions

These results showed that switching patients from IVIG to SCIG improves patient self-reported health status and IgG-specific HRQOL perception. The maintenance studies generally showed no deterioration of this improved health status over a long follow-up period.

     

Flebogamma<Superscript>®</Superscript> 5 % DIF Intravenous Immunoglobulin for Replacement Therapy in Children with Primary Immunodeficiency Diseases

Purpose

The previous studies with Flebogamma^® 5 % DIF intravenous immunoglobulin (IVIG) contained insufficient numbers of pediatric subjects to fully warrant a pediatric indication by the FDA. The objective of this study was to evaluate the efficacy, safety, and pharmacokinetics of Flebogamma® 5 % DIF for replacement therapy in children (age 2–16) with primary immunodeficiency diseases (PIDD).

Methods

IVIG was administered at eight clinical sites to 24 subjects with well-defined PIDD at a dose of 300–800 mg/kg every 21–28 days for 12 months. The pharmacokinetics endpoint in this study was the dose-adjusted increment of the serum IgG trough levels.

Results

The calculated serious bacterial infection rate was 0.05/subject/year. The incidence of adverse events considered potentially related to IVIG during or within 72 h after completing an infusion was within the FDA guidance threshold of <40 % at each time point. Dose-adjusted incremental IgG levels remained approximately equal to or slightly greater than pre-study IgG levels (between 800 and 1000 mg/dL throughout) when the subjects were treated with IVIG therapy other than Flebogamma^® DIF 5 % indicating no evidence of a different pharmacokinetic profile in this pediatric population if compared to those profiles in previous Flebogamma studies in predominately adult populations.

Conclusions

Flebogamma^® 5 % DIF is efficacious and safe, has adequate pharmacokinetic properties, is well-tolerated, and maintains the profile of Flebogamma^® 5 % for the treatment of children with primary humoral immunodeficiency diseases.

     

Safety and Efficacy of Privigen®, a Novel 10% Liquid Immunoglobulin Preparation for Intravenous Use,in Patients with Primary Immunodeficiencies

Purpose

The present study was designed to evaluate the efficacy and safety of a novel, 10% liquid formulation of intravenous immunoglobulin, stabilized with 250 mmol/L l-proline (Privigen®), in patients with primary immunodeficiency disease.

Materials and Methods

Eighty adults and children diagnosed with common variable immunodeficiency or X-linked agammaglobulinemia received intravenous Privigen® infusions (200–888 mg/kg) at 3- or 4-week intervals over a 12-month period, according to their previously established maintenance dose. The primary endpoint was the annual rate of acute serious bacterial infections.

Results

There were six episodes of acute serious bacterial infections, corresponding to an annual rate of 0.08; the annual rate for all infections was 3.55. Mean serum IgG trough levels were between 8.84 and 10.27 g/L. A total of 1,038 infusions were administered, most of them at the maximum rate permitted (8.0 mg kg^?1 min^?1). Temporally associated adverse events, possibly or probably related to study drug, occurred in 9% of infusions, either during or within 72 h after infusion end.

Conclusion

Privigen® is well tolerated and effective for the treatment of primary immunodeficiency.

     

Is Tamsulosin 0.2 mg Effective and Safe as a First-Line Treatment Compared with Other Alpha Blockers?: A Meta-Analysis and a Moderator Focused Study

PurposeTamsulosin 0.2 mg is used widely in Asian people, but the low dose has been studied less than tamsulosin 0.4 mg or other alpha blockers of standard dose. This study investigated the efficacy and safety of tamsulosin 0.2 mg by a meta-analysis and meta-regression.ResultsTen studies were included with a total sample size of 1418 subjects [722 tamsulosin 0.2 mg group and 696 other alpha-blockers (terazosin, doxazosin, naftopidil, silodosin) group]. Study duration ranged from 4 to 24 weeks. The pooled overall standardized mean differences (SMD) in the mean change of IPSS from baseline for the tamsulosin group versus the control group was 0.02 [95% confidence interval (CI); -0.20, 0.25]. The pooled overall SMD in the mean change of QoL from baseline for the tamsulosin group versus the control group was 0.16 (95% CI; -0.16, 0.48). The regression analysis with the continuous variables (number of patients, study duration) revealed no significance in all outcomes as IPSS, QoL, and Qmax.ConclusionThis study clarifies that tamsulosin 0.2 mg has similar efficacy and fewer adverse events compared with other alpha-blockers as an initial treatment strategy for men with lower urinary tract symptoms.     

Efficacy,Safety, and Pharmacokinetics of a Novel Human Immune Globulin Subcutaneous, 20 % in Patients with Primary Immunodeficiency Diseases in North America

Patients with primary immunodeficiency disease (PIDD) typically require life-long intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig) replacement therapy to prevent recurrent infections. The efficacy, safety, and pharmacokinetics of a highly concentrated (20 %) Ig preparation for SC administration (IGSC 20 %) were evaluated in a prospective trial in patients with PIDD. A total of 74 patients (aged 3–83 years) received 4327 IGSC 20 % infusions over a median of 380.5 days. The rate of validated serious bacterial infections was 0.012 event/patient-year (p?<?0.0001 compared with the historical control), and the annualized rate of infection was 2.41 events/patient. Median IgG trough levels were >14.5 g/l. The median maximum infusion rate was 60 ml/h/site (range 4.4–180), resulting in a median infusion duration of 0.95 h. A volume ≥30 ml was infused per site in 74.8 % of IGSC 20 % infusions. Most (84.9 %) infusions were administered using ≤2 infusion sites; for 99.8 % of infusions, there was no need to interrupt/stop administration or reduce the infusion rate. No related serious adverse event (AE) occurred during IGSC 20 % treatment; related non-serious AEs occurred at a rate of 0.036 event/infusion. The incidence of related local AEs was 0.015 event/infusion and of related systemic AEs was 0.021 event/infusion; most were mild in severity, none severe. Increased infusion rates or volumes were not associated with higher AE rates. The investigated IGSC 20 % treatment was shown to be effective and safe, enabling higher infusion rates and volumes per site compared to conventional SC treatments, resulting in fewer infusion sites and shorter infusion durations.     

Is High-Dose Leuprorelin Acetate Effective and Safe in Asian Men with Prostate Cancer? An Open-Label,Non-Comparative,Multi-Center Clinical Trial

Purpose

Leuprorelin is a well known luteinizing hormone releasing hormone agonist. However, there are insufficient data on the efficacy and safety of high dose leuprorelin acetate, especially in Asian patients with prostate cancer. We aimed to investigate the safety and efficacy of leuprorelin acetate 22.5 mg administered at three-month intervals in patients with prostate cancer.

Materials and Methods

In an open, prospective clinical trial enrolling 47 patients, we aimed to assess the efficacy and safety of leuprorelin acetate 22.5 mg in treating patients with histologically confirmed prostate cancer. The primary objective of this study was to evaluate the efficacy of the leuprorelin acetate 22.5 mg in producing and maintaining castration levels of testosterone over a 6-month follow-up period and to determine its safety profile.

Results

All 42 patients achieved serum testosterone levels within the castration range by 4 weeks. A breakthrough response was observed in one of 36 patients by 8 weeks. However, this patient was medically castrated by 12 weeks. There were no significant prostate-specific antigen (PSA) or testosterone changes according to clinical stage or body mass index. Twenty adverse events (AEs) in 15 of 42 patients (35.7%) were observed during this study. The most common AEs were hot flushes (n=4, 20.0%) with mild intensity, pain (n=2, 10.0%), and infection (n=2, 10.0%). No patient withdrew from the study due to AEs.

Conclusion

Leuprorelin acetate 22.5 mg was shown to be effective and safe in Asian patients with prostate cancer, even though sexual function decreased.     

Efficacy,Safety, and Tolerability of Long-Term Combination Antiretroviral Therapy in Asymptomatic Treatment-Naïve Adults with Early HIV Infection

Abstract

Background: Initiating antiretroviral therapy in the early stages of HIV infection may afford benefits over delaying treatment. We evaluated the long-term efficacy and tolerrability of indinavir, zidovudine, and lamivudine begun in asymptomatic treatment-naïve adults with baseline CD4 counts ≥500 cells/mm³ and HIV (v)RNA levels >1000 copies/mL in an open-label, noncomparative study. Method: Proportions of participants with suppressed viremia were assessed using observed data, a model derived from generalized estimating equations counting only treatment-related discontinuations as failures (TRD=F), and a strict intention-to-treat analysis counting all noncompleters as failures (NC=F). Results: 199 participants (median age 34; 79% men; 61% White) with a median CD4 count of 574 (range 130-1204) cells/mm³ and vRNA level of 3.89 (range 2.30-6.50) log₁₀ copies/mL were followed up to 319 weeks. Overall, 142 participants (71%) discontinued the study after a median time of 112 weeks, including 4 (2%) due to unsuppressed viremia and 40 (20%) due to adverse events. After 156 weeks, 98%, 76%, and 53% of participants achieved <400 vRNA copies/mL based on observed data, TRD=F, and NC=F analyses, respectively; corresponding percentages <50 copies/mL were 93%, 72%, and 51%. Mean CD4 count increased by >250 cells/mm³ from baseline. Nausea (69%), fatigue (49%), diarrhea (37%), headache (28%), abdominal pain (28%), hematuria (27%), flank pain (26%), and hyperbilirubinemia (25%) were the most common drug-related adverse events. Conclusion: A minority of participants in this study completed follow-up. Despite durable HIV suppression in most participants remaining on treatment, treatment fatigue may interfere with long-term therapy in asymptomatic HIV-infected patients.     

Safety, Efficacy, and Pharmacokinetics of Flebogamma® 5% [Immune Globulin Intravenous (Human)] for Replacement Therapy in Primary Immunodeficiency Diseases

The purpose of the study was to evaluate the safety, efficacy, and pharmacokinetics of Flebogamma 5%, an immune globulin intravenous product, for replacement therapy in primary immunodeficient patients. The US Food and Drug Administration has proposed that the use of new products must result in < or =1 serious bacterial infection/subject/year, have acceptable safety and tolerability, and have pharmacokinetic properties similar to endogenous IgG and other commercially available immune globulin products. Flebogamma 5% was administered at seven clinical sites to 51 subjects aged 14-74 years with well-defined primary immunodeficiency diseases at a dose of 300-600 mg/kg every 21-28 days for 12 months. The calculated serious infection rate for the intent-to-treat population was 0.061/subject/year. The incidence of adverse events considered potentially related to Flebogamma 5%, and occurring during or within 72 h after completing the infusion was approximately 8%. The half-life of total IgG was 37 days. Flebogamma 5% is efficacious, safe, and well-tolerated, and does not put subjects at increased risk of adverse events other than those that could be reasonably expected in primary immunodeficient subjects who are receiving any immune globulin product.     

Elastase, α1-Proteinase Inhibitor,and Interleukin-8 in Children and Young Adults with End-Stage Kidney Disease Undergoing Continuous Ambulatory Peritoneal Dialysis

Peritoneal dialysis is one of the main modality of treatment in end-stage kidney diseases (ESKD) in children. In our previous work in chronic kidney disease patients, in pre-dialyzed period and on hemodialysis, the neutrophils were highly activated. The aim of this study was to assess an inflammatory condition and neutrophil activation in ESKD patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Thirteen CAPD patients without infection, both sexes, aged 2.5–24 years, and group of healthy subjects (C) were studied. For comparative purposes the conservatively treated (CT) group of ESKD patients was included. Neutrophil elastase in complex with α₁-proteinase inhibitor (NE-α₁PI; ELISA), α₁-proteinase inhibitor (α₁PI; radial immunodiffusion) and interleukin-8 (IL-8; ELISA) were measured in the blood samples from CAPD, CT, and C group and in the peritoneal dialysate fluid (PDF) samples of patients on CAPD. A significantly increased plasma NE-α₁PI levels (median 176.5 μg/L, range 85.2–373.2 μg/L; p < 0.00005), serum IL-8 (median 18.6 pg/mL, range 15.73–35.28 pg/mL; p < 0.05), and slightly decreased serum α₁PI (median 1,540 mg/L, range 1,270–1,955; p ≤ 0.05) compared to the control groups were found. There were no significant differences of analyzed parameters between CAPD and CT patients. The concentration ratio of NE-α₁PI, α₁PI and IL-8 in blood/PDF was 29.97, 8.24, and 4.48, respectively. There were significantly positive correlations between serum and PDF concentration of α₁PI and IL-8 (r = 0.613, p < 0.05; r = 0.59; p < 0.005, respectively). The results of our study demonstrate that neutrophils are highly activated in non-infected CAPD patients. The pivotal marker of this activation is NE-α₁PI. It may contribute to chronic inflammation and tissues injury.     

Food Neophobia in Young Adults: Genetic Architecture and Relation to Personality,Pleasantness and Use Frequency of Foods,and Body Mass Index—A Twin Study

Food neophobia has been studied extensively in children, but its causal origins and relationship to eating behavior in adults are not well understood. We studied genetic and environmental effects on variation in food neophobia, measured using the Food Neophobia Scale, and explored associations between food neophobia and personality, pleasantness and use frequency of food groups, and body mass index in young adult twins (N = 1175, aged 20–25 years, 54.7% women). In women, additive genetic effects (heritability) accounted for 61% of variation in food neophobia, whereas in men, shared environmental effects explained 45% of the variation. Food neophobia negatively correlated with the personality trait Openness, corrected for the structural overlap (r = −0.23), and in women, these two traits had a genetic correlation (r _g = −0.39). In addition, food neophobia negatively correlated with pleasantness and use frequency of fruits and vegetables and of fish and with mean pleasantness of foods. Once evolutionarily important, food neophobia should at present be considered in nutrition counseling as a possible barrier to a balanced diet.     

Octagam® 5%, an Intravenous IgG Product, Is Efficacious and Well Tolerated in Subjects with Primary Immunodeficiency Diseases

Octagam is an intravenous immunoglobulin preparation registered in Europe for treating primary immunodeficiency diseases (PID). The present clinical trial was designed to demonstrate that Octagam meets the minimal efficacy requirement of the U.S. Food and Drug Administration-that treatment should result in 相似文献   

Interaction between Socioeconomic Status and Cognitive Development in Children Aged 7, 9, and 11 Years: A Cross-Sectional Study

The socioeconomic status (SES) of parents has a crucial influence on the cognitive development of children, but it is not clear whether this effect varies as a function of the children’s age. The objective of this study was to investigate the development of children aged 7, 9, and 11 years of parents with extremely low SES in a developing country (Ecuador). Participating children were divided between a medium-SES group and a low-SES group. Statistically significant differences were observed as a function of SES group and age in verbal memory, language, and executive function, observing wider between-group differences among the 11-year-olds.     

Changing Patterns in the Incidence and Survival of Thyroid Cancer with Follicular Phenotype—Papillary, Follicular, and Anaplastic: A Morphological and Epidemiological Study

Thyroid carcinomas with follicular phenotype have demonstrated changing patterns over 30 years (1973–2003) according to data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Papillary carcinomas have significantly increased. They accounted for 74% of all cases of thyroid cancers in 1973 and 87% in 2003. During this period, the incidence rate of papillary carcinoma (including the follicular variant) increased by 189%, the rate of follicular carcinoma remained stable, and the rate of anaplastic carcinoma decreased by 22%. The rate of the follicular variant of papillary carcinoma alone increased by 173%. Thyroid cancer was more common in whites than in blacks and in females more than in males. Papillary carcinomas rapidly increased during adolescence and reached a peak around age 52–56, then declined. Follicular carcinomas increased steadily, but at a lower rate until age 80. After 1988, both papillary and follicular carcinomas, less than 2 cm, increased at the same rate as carcinomas larger than 2 cm. However, papillary carcinomas less than 2 cm were more common. Overall, the 10-year relative survival rate was greater than 90% for blacks and whites with the exception of follicular carcinoma in blacks. The 10-year relative survival rate for anaplastic carcinoma in patients over 40 years of age was 4.7%. The decrease in incidence rate of anaplastic carcinoma may be the result of the successful treatment of papillary and follicular carcinomas.     

A Phase II,Multicenter, Single-Arm Study to Evaluate the Safety and Efficacy of Deferasirox after Hematopoietic Stem Cell Transplantation in Children with β-Thalassemia Major

We conducted a prospective, phase II, multicenter, single-arm study to evaluate the efficacy and safety of deferasirox in patients age >2 to <18 years with β-thalassemia major (TM) who underwent hematopoietic stem cell transplantation (HSCT) and had evidence of iron overload (serum ferritin >1000?µg/L; cardiac MRI T2*?<20?ms, or liver iron concentration [LIC; by MRI R2]? ≥5?mg/g). Patients received deferasirox at an initial dose of 10?mg/kg/day, with up-titration to a maximum of 20?mg/kg/day. The study continued for 52 weeks and included a total of 27 patients (mean age, 9.1?±?3.8 years; 70.4% male). One patient (3.7%) was lost to follow-up. The majority of patients (n?=?20; 74.1%) were able to achieve the intended dose of 20?mg/kg/day. No deaths occurred. A total of 134 adverse events (AEs) were reported in 25 patients (92.6%) during the study. The majority of patients had grade 1 or 2 AEs, with only 8 patients (29.6%) experiencing grade 3 AEs. Only 10 AEs occurring in 4 patients (14.8%) were suspected to be related to deferasirox (ALT/AST increase, n?=?4; urinary tract infection, n?=?1). The deferasirox dose had to be adjusted or interrupted for 6 AEs occurring in 4 patients (14.8%). A total of 6 serious AEs occurred in 3 patients (11.1%), none of which were suspected to be related to deferasirox. From baseline to week 52, there were decreases in median concentrations of alanine aminotransferase (ALT), from 30.0 to 17.0?IU/L, and aspartate aminotransferase (AST), from 35.5 to 26.0?IU/L. Median serum creatinine and cystatin C concentrations were similar at baseline and week 52. There was a continuous and significant decrease in median serum ferritin level from 1718.0?µg/L at baseline to 845.3?µg/L following 52 weeks of therapy (P?<?.001); 9 patients (33.3%) achieved a level of <500?µg/L. There was also a significant decrease in median LIC (from 8.6 to 4.1?mg/g; P?<?.001) and an increase in median cardiac T2* (from 26.0 to 28.0?ms; P?=?.520) from baseline to week 52. Our findings indicate that deferasirox treatment at doses up to 20?mg/kg/day reduces the iron burden in children with TM post-HSCT, with a manageable safety profile.     

Post-Transplant CD34+ Selected Stem Cell “Boost” for Mixed Chimerism after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation in Children and Young Adults with Primary Immune Deficiencies

Mixed chimerism and eventual graft loss occurs in a proportion of children with primary immune deficiencies receiving alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens before allogeneic hematopoietic stem cell transplantation (HSCT). We investigated the usefulness of a CD34⁺ selected stem cell “boost” without conditioning to treat mixed chimerism in children and young adults who received predominantly an alemtuzumab, fludarabine, and melphalan RIC regimen for primary immune deficiencies and reported the outcomes. Patients with a primary immune deficiency disorder who were either enrolled on a prospective CD34⁺ boost study for treatment of mixed chimerism from 2011 to 2014 (n = 9) or treated with a CD34⁺ boost on a clinical basis from 2014 to 2016 (n = 3) were included in this analysis. Response to a CD34⁺ boost was defined as a rise in donor chimerism by ≥15% with donor chimerism of at least 20%, stabilization was defined as a rise in chimerism by <15% with donor chimerism ≥ 20%, and no response was defined as any decline in donor chimerism or need for a second HSCT after a CD34⁺ boost. Twelve patients received alemtuzumab, fludarabine, and melphalan. Median age was 4.5 years (range, .9 to 20.6), and median whole blood donor chimerism before the boost was 25% (range, 3% to 61%). Three patients (25%) met criteria for response, 1 patient (8%) was considered to have stabilization, and 8 patients (67%) had no response 12 months after the boost. None of the patients developed any complications from a CD34⁺ boost, including no acute graft-versus-host disease (GVHD). All patients are alive with a median follow-up of 32 months (range, 8 to 79). We conclude that a CD34⁺ selected stem cell boost can be considered for treatment of mixed chimerism after alemtuzumab, fludarabine, and melphalan RIC HSCT in children and young adults with primary immune deficiencies. Approximately one-third of patients can be expected to benefit from a CD34⁺ selected stem cell boost and may avoid the need for a second HSCT. Lack of any GVHD or toxicity makes a stem cell boost an attractive option compared with donor lymphocyte infusions for treatment of mixed chimerism.     

Efficacy and Safety of Hizentra<Superscript>®</Superscript>, a New 20% Immunoglobulin Preparation for Subcutaneous Administration,in Pediatric Patients with Primary Immunodeficiency

Subcutaneous IgG treatment for primary immunodeficiencies (PI) is particularly well suited for children because it does not require venous access and is mostly free of systemic adverse events (AEs). In a prospective, open-label, multicenter, single-arm, Phase III study, 18 children and five adolescents with PI were switched from previous intravenous (IVIG) or subcutaneous (SCIG) IgG treatment to receive dose-equivalent, weekly subcutaneous infusions of Hizentra^® for 40 weeks. Mean IgG trough levels were maintained in patients previously on SCIG, or increased in those previously on IVIG, regardless of age. No serious bacterial infections were reported during the efficacy period of the study. The rates of non-serious infections were 4.77 (children) and 5.18 (adolescents) infections per patient per year. Related AEs were observed in seven children (38.9%) and two adolescents (40%). Three serious AEs and two AEs leading to discontinuation (all unrelated) were reported in children. Hizentra^® is an effective and well-tolerated treatment for pediatric patients.