Subcutaneous Immunoglobulin 16.5% (Cutaquig®) in Primary Immunodeficiency Disease: Safety, Tolerability, Efficacy, and Patient Experience with Enhanced Infusion Regimens.

PURPOSE: To achieve reductions in infusion time, infusion sites, and frequency, a prospective, open-label, multicenter, Phase 3 study evaluated the safety, efficacy, and tolerability of subcutaneous immunoglobulin (SCIG) 16.5% (Cutaquig®, Octapharma) at enhanced infusion regimens. METHODS: Three separate cohorts received SCIG 16.5% evaluating volume, rate, and frequency: Cohort 1) volume assessment/site: up to a maximum 100 mL/site; Cohort 2) infusion flow rate/site: up to a maximum of 100 mL/hr/site or the maximum flow rate achievable by the tubing; Cohort 3) infusion frequency: every other week at twice the patient's weekly dose. RESULTS: For Cohort 1 (n = 15), the maximum realized volume per site was 108 mL/site, exceeding the currently labeled (US) maximum (up to 40 mL/site for adults). In Cohort 2 (n = 15), the maximum realized infusion flow rate was 67.5 mL/hr/site which is also higher than the labeled (US) maximum (up to 52 mL/hr/site). In Cohort 3 (n = 34), the mean total trough levels for every other week dosing demonstrated equivalency to weekly dosing (p value = 0.0017). All regimens were well tolerated. There were no serious bacterial infections (SBIs). Most patients had mild (23.4%) or moderate (56.3%) adverse events. The majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens and reported that switching to SCIG 16.5% was easy. CONCLUSIONS: SCIG 16.5% (Cutaquig®), infusions are efficacious, safe, and well tolerated with reduced infusion time, fewer infusion sites, and reduced frequency. Further, the majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens.

Subcutaneous immunoglobulin 16.5% for the treatment of pediatric patients with primary antibody immunodeficiency.

INTRODUCTION: Human immunoglobulin (IG) administered intravenously (IVIG) or subcutaneously (SCIG) is used to prevent infections in patients with primary immunodeficiency diseases (PIDDs) such as primary antibody immunodeficiencies. AREAS COVERED: This review provides an overview of PIDD with a focus on SCIG treatment, including the properties and clinical trial results of a new SCIG 16.5% (Cutaquig, Octapharma) in pediatric patients. We also discuss the various benefits of SCIG including stable serum immunoglobulin G levels, high tolerability with fewer systemic side effects, and the flexibility of self-administration. EXPERT OPINION: Individualized treatment for PIDD in children is necessary given the different factors that affect administration of SCIG. Variables such as the dose, dosing interval, administration sites, and ancillary equipment can be adjusted to impact the long-term satisfaction with SCIG administration in pediatric patients. The successful work that has been conducted by both professional and patient organizations to increase awareness of PIDD, especially in pediatric patients, is substantial and ongoing. The importance of early diagnosis and treatment in the pediatric patient population cannot be overstated. The safety, efficacy, and tolerability of SCIG 16.5% have been demonstrated in pediatric patients with PIDDs providing an additional therapeutic option in this vulnerable population.

Human immunoglobulin (IG) is extracted from the plasma of donors as a sterile, purified blood product that is administered intravenously (via a vein [IVIG]) or subcutaneously (under the skin [SCIG]) and is used for a variety of disorders, including the prevention of infections in patients with primary immunodeficiency diseases (PIDDs) such as primary antibody immunodeficiencies. This review provides an overview of PIDD with a focus on SCIG treatment, including the properties and clinical trial results of a new SCIG 16.5% (Cutaquig, Octapharma) in pediatric patients. We also discuss the various benefits of SCIG including stable serum immunoglobulin G levels, high tolerability with fewer systemic side effects, and the flexibility of self-administration. The importance of early identification of PIDD, especially in pediatric patients, cannot be overstated to ensure prompt treatment. The safety, efficacy, and tolerability of SCIG 16.5% have been demonstrated in pediatric patients with PIDDs providing an additional therapeutic option in this vulnerable population.

Long-term efficacy, safety, and tolerability of a subcutaneous immunoglobulin 16.5% (cutaquig®) in the treatment of patients with primary immunodeficiencies.

A prospective study and its long-term extension examined whether weekly treatment of patients with primary immunodeficiencies (PIDs) with a 16.5% subcutaneous immunoglobulin (SCIg; cutaquig®) confers acceptable efficacy, safety, and tolerability over a follow-up of up to 238 weeks (>4 years). Seventy-five patients received 4462 infusions during up to 70 weeks of follow-up in the main study and 27 patients received 2777 infusions during up to 168 weeks of follow-up in the extension. In the main study, there were no serious bacterial infections (SBIs), and the annual rate of other infections was 3.3 (95% CI 2.4, 4.5). One SBI was recorded in the extension, for an SBI rate of 0.02 (upper 99% CI 0.19). The annual rate of all infections over the duration of the extension study was 2.2 (95% CI 1.2, 3.9). Only 15.0% (1085) of 7239 infusions were associated with infusion site reactions (ISRs), leaving 85.0% (6153) of infusions without reactions. The majority of ISRs were mild and transient. ISR incidence decreased over time, from 36.9% to 16% during the main study and from 9% to 2.3% during the extension. The incidence of related systemic adverse events was 14.7% in the main study and 7.4% in the extension. In conclusion, this prospective, long-term study with cutaquig showed maintained efficacy and low rates of local and systemic adverse reactions in PID patients over up to 238 weeks of follow-up.

Overview of subcutaneous immunoglobulin 16.5% in primary and secondary immunodeficiency diseases.

Most primary immunodeficiency diseases, and select secondary immunodeficiency diseases, are treated with immunoglobulin (IG) therapy, administered intravenously or subcutaneously (SCIG). The first instance of IG replacement for primary immunodeficiency disease was a 16.5% formulation administered subcutaneously in 1952. While most SCIG products are now a 10 or 20% concentration, this review will focus on SCIG 16.5% products with a historical overview of development, including the early pioneers who initiated and refined IG replacement therapy, as well as key characteristics, manufacturing and clinical studies. In determining an appropriate IG regimen, one must consider specific patient needs, characteristics and preferences. There are advantages to SCIG, such as stable serum immunoglobulin G levels, high tolerability and the flexibility of self-administered home treatment.

Plain language summary Primary immunodeficiency diseases, and select secondary immunodeficiency diseases, weaken the immune system, allowing infections and other health problems to occur more easily. Some patients require treatments to boost their immune system, such as immunoglobulin (IG) therapy, which can be either injected via a needle into a vein (intravenously) or inserted underneath the skin (subcutaneously; SCIG). The first instance of IG treatment for primary immunodeficiency disease was a 16.5% SCIG product given in 1952. While most SCIG products are now a 10 or 20% concentration, this review will focus on SCIG 16.5% products with a historical overview of development, including the early pioneers who initiated and refined IG therapy, as well as key characteristics, manufacturing and clinical studies. In determining an appropriate IG regimen, one must consider specific patient needs, characteristics and preferences. There are advantages to SCIG, such as stable serum immunoglobulin G levels, high tolerability and the flexibility of self-administered home treatment.

Intra-operative Use of Hemopatch®: Interim Results of a Nationwide European Survey of Surgeons.

INTRODUCTION: Haemostasis is a critical part of surgery. Haemostatic agent selection is based upon a number of factors including surgeon's experience and choice. This post-marketing survey determined surgeons' intraoperative use and perception of Hemopatch® (Baxter Healthcare Corporation, Deerfield, IL), a resorbable collagen-based sealing haemostat. METHODS AND PARTICIPANTS: A one-arm questionnaire was distributed to European general, cardiac, pulmonary, and urologic surgeons who used Hemopatch® to achieve haemostasis in situations where bleeding control by pressure, ligature, or conventional procedures had been ineffective or was impractical. Responses were summarized for patient characteristics, surgical procedures/techniques, and surgeons' assessment of Hemopatch® regarding their overall satisfaction and utilization characteristics of Hemopatch®. RESULTS: Of 1028 responses received from seven European countries, the majority were from Germany (47.3%) or Italy (36%). Most cases were in males (60.7%), 50-75 years of age (61.8%), performed by an open approach (82.5%), with 52.7% general-, 16.2% cardiac-, 7.5% lung, 19.5% urologic-type procedures and 3.7% other/unknown. Successful haemostasis after two minutes of approximation occurred in 93.3% of patients (86.8%-96.9% across surgical subtypes), with similar rates by approach (93.1% open; 94.1% minimally-invasive), and patient's use of anticoagulant and/or antiplatelet agents (87.9% - 93.1%). Over 92% of surgeon's rated Hemopatch® as "excellent" or "good" in assessments of overall satisfaction, haemostasis efficacy, ease of preparation, ease of handling, flexibility/pliability, and tissue adherence. These characteristics were rated as excellent or good by 81% or more of surgeons in analyses by surgical subspecialty and surgical approach of open or minimally invasive. CONCLUSIONS: Hemopatch® provides effective haemostasis across a variety of surgical procedures, both in open- and minimally-invasive, as well as in patients receiving anticoagulant and/or antiplatelet agents. Surgeon's generally rated their overall satisfaction with Hemopatch®, its haemostatic efficacy, and other characteristics as "much better" or "better" than their previously used haemostat.

Hospital economic impact from hemostatic matrix usage in cardiac surgery.

OBJECTIVE: Improved health outcomes can result in economic savings for hospitals and payers. While effectiveness of topical hemostatic agents in cardiac surgery has been demonstrated, evaluations of their economic benefit are limited. This study quantifies the cost consequences to hospitals, based on clinical outcomes, from using a flowable hemostatic matrix vs non-flowable topical hemostatic agents in cardiac surgery. RESEARCH DESIGN AND METHODS: Applying clinical outcomes from a prospective randomized clinical trial, a cost consequence framework was utilized to model the economic impact of comparator groups. From that study, clinical outcomes were obtained and analyzed for a flowable hemostatic matrix (FLOSEAL, Baxter Healthcare Corporation) vs non-flowable topical hemostats (SURGICEL Nu-Knit, Ethicon-Johnson & Johnson; GELFOAM, Pfizer). Costing analyses focused on the following outcomes: complications, blood transfusions, surgical revisions, and operating room (OR) time. Cardiac surgery costs were analyzed and expressed in 2012 US dollars based on available literature searches and US data. Comparator group variability in cost consequences (i.e., cost savings) was calculated based on annualized impact and scenario testing. RESULTS: RESULTS suggest that if a flowable hemostatic matrix (rather than a non-flowable hemostat) was utilized exclusively in 600 mixed cardiac surgeries annually, a hospital could improve patient outcomes by a reduction of 33 major complications, 76 minor complications, 54 surgical revisions, 194 transfusions, and 242 h of OR time. These outcomes correspond to a net annualized cost consequence savings of $5.38 million, with complication avoidance as the largest contributor. CONCLUSIONS: This cost consequence framework and supportive modeling was used to evaluate the hospital economic impact of outcomes resulting from the usage of various hemostatic agents. These analyses support that cost savings can be achieved from routine use of a flowable hemostatic matrix, rather than a non-flowable topical hemostat, in cardiac surgery.

Comparison of hemostatic matrix and standard hemostasis in patients undergoing primary TKA.

Bleeding after total knee arthroplasty increases the risk of pain, delayed rehabilitation, blood transfusion, and transfusion-associated complications. The authors compared pre- and postoperative decreases in hemoglobin as a surrogate for blood loss in consecutive patients treated at a single institution by the same surgeon (J.L.C.) using conventional hemostatic methods (electrocautery, suturing, or manual compression) or a gelatin and thrombin-based hemostatic matrix during total knee arthroplasty. Data were collected retrospectively by chart review. The population comprised 165 controls and 184 patients treated with hemostatic matrix. Median age was 66 years (range, 28-89 years); 66% were women. The arithmetic mean ± SD for the maximal postoperative decrease in hemoglobin was 3.18 ± 0.94 g/dL for controls and 2.19 ± 0.83 g/dL for the hemostatic matrix group. Least squares means estimates of the group difference (controls-hemostatic matrix) in the maximal decrease in hemoglobin was 0.96 g/dL (95% confidence interval, 0.77-1.14 mg/dL; P<.0001). Statistically significant covariate effects were observed for preoperative hemoglobin level (P<.0001) and body mass index (P=.0029). Transfusions were infrequent in both groups. The frequency of acceptable range of motion was high (control, 88%; hemostatic matrix, 84%). In both groups, overall mean tourniquet time was approximately 1 hour, and the most common length of stay was 3 to 5 days. No serious complications related to the hemostatic agent were observed. These data demonstrate that the use of a flowable hemostatic matrix results in less reduction in hemoglobin than the use of conventional hemostatic methods in patient undergoing total knee arthroplasty.

Prospective randomized trial of LC+LCBDE vs ERCP/S+LC for common bile duct stone disease.

OBJECTIVE: To compare outcome parameters for good-risk patients with classic signs, symptoms, and laboratory and abdominal imaging features of cholecystolithiasis and choledocholithiasis randomized to either laparoscopic cholecystectomy plus laparoscopic common bile duct exploration (LC+LCBDE) or endoscopic retrograde cholangiopancreatography sphincterotomy plus laparoscopic cholecystectomy (ERCP/S+LC). DESIGN: Our study was a prospective trial conducted following written informed consent, with randomization by the serially numbered, opaque envelope technique. SETTING: Our institution is an academic teaching hospital and the central receiving and trauma center for the City and County of San Francisco, California. PATIENTS: We randomized 122 patients (American Society of Anesthesiologists grade 1 or 2) meeting entry criteria. Ten of these patients, excluded from outcome analysis, were protocol violators having signed out of the hospital against medical advice before 1 or both procedures were completed. INTERVENTIONS: Treatment was preoperative ERCP/S followed by LC, or LC+LCBDE. MAIN OUTCOME MEASURES: The primary outcome measure was efficacy of stone clearance from the common bile duct. Secondary end points were length of hospital stay, cost of index hospitalization, professional fees, hospital charges, morbidity and mortality, and patient acceptance and quality of life scores. RESULTS: The baseline characteristics of the 2 randomized groups were similar. Efficacy of stone clearance was likewise equivalent for both groups. The time from first procedure to discharge was significantly shorter for LC+LCBDE (mean [SD], 55 [45] hours vs 98 [83] hours; P < .001). Hospital service and total charges for index hospitalization were likewise lower for LC+LCBDE, but the differences were not statistically significant. The professional fee charges for LC+LCBDE were significantly lower than those for ERCP/S+LC (median [SD], $4820 [1637] vs $6139 [1583]; P < .001). Patient acceptance and quality of life scores were equivalent for both groups. CONCLUSIONS: Both ERCP/S+LC and LC+LCBDE were highly effective in detecting and removing common bile duct stones and were equivalent in overall cost and patient acceptance. However, the overall duration of hospitalization was shorter and physician fees lower for LC+LCBDE. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00807729.

The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen.

The maintenance of T cell tolerance in the periphery proceeds through several mechanisms, including anergy, immuno-regulation, and deletion via apoptosis. We examined the mechanism underlying the induction of CD8 T cell peripheral tolerance to a self-Ag expressed on pancreatic islet beta-cells. Following adoptive transfer, Ag-specific clone 4 T cells underwent deletion independently of extrinsic death receptors, including Fas, TNFR1, or TNFR2. Additional experiments revealed that the induction of clone 4 T cell apoptosis during peripheral tolerance occurred via an intrinsic death pathway that could be inhibited by overexpression of Bcl-2 or targeted deletion of the proapoptotic molecule, Bim, thereby resulting in accumulation of activated clone 4 T cells. Over-expression of Bcl-2 in clone 4 T cells promoted the development of effector function and insulitis whereas Bim-/- clone 4 cells were not autoaggressive. Examination of the upstream molecular mechanisms contributing to clone 4 T cell apoptosis revealed that it proceeded in a p53, E2F1, and E2F2-independent manner. Taken together, these data reveal that initiation of clone 4 T cell apoptosis during the induction of peripheral tolerance to a cross-presented self-Ag occurs through a Bcl-2-sensitive and at least partially Bim-dependent mechanism.

The virtual NOD mouse: applying predictive biosimulation to research in type 1 diabetes.

Type 1 diabetes is a complex, multifactorial disease characterized by T cell-mediated autoimmune destruction of insulin-secreting pancreatic beta cells. To facilitate research in type 1 diabetes, a large-scale dynamic mathematical model of the female non-obese diabetic (NOD) mouse was developed. In this model, termed the Entelos Type 1 Diabetes PhysioLab platform, virtual NOD mice are constructed by mathematically representing components of the immune system and islet beta cell physiology important for the pathogenesis of type 1 diabetes. This report describes the scope of the platform and illustrates some of its capabilities. Specifically, using two virtual NOD mice with either average or early diabetes-onset times, we demonstrate the reproducibility of experimentally observed dynamics involved in diabetes progression, therapeutic responses to exogenous IL-10, and heterogeneity in disease onset. Additionally, we use the Type 1 Diabetes PhysioLab platform to investigate the impact of disease heterogeneity on the effectiveness of exogenous IL-10 therapy to prevent diabetes onset. Results indicate that the inability of a previously published IL-10 therapy protocol to protect NOD mice who exhibit early diabetes onset is due to high levels of pancreatic lymph node (PLN) inflammation, islet infiltration, and beta cell destruction at the time of treatment initiation. Further, simulation indicates that earlier administration of the treatment protocol can prevent NOD mice from developing diabetes by initiating treatment during the period when the disease is still sensitive to IL-10's protective function.

Dosing and timing effects of anti-CD40L therapy: predictions from a mathematical model of type 1 diabetes.

Several publications describing the use of anti-CD40L monoclonal antibodies (anti-CD40L) for the treatment of type 1 diabetes in non-obese diabetic (NOD) mice have reported different treatment responses to similar protocols. The Entelos Type 1 Diabetes PhysioLab platform, a dynamic large-scale mathematical model of the pathogenesis of type 1 diabetes, was used to study the effects of anti-CD40L therapy in silico. An examination of the impact of pharmacokinetic variability and the heterogeneity of disease progression rate on therapeutic outcome provided insights that could reconcile the apparently conflicting data. Optimal treatment protocols were identified by exploring the dynamics of key pathophysiological pathways.

Mechanisms mediating anti-CD3 antibody efficacy: insights from a mathematical model of type 1 diabetes.

Anti-CD3 antibody therapy, a promising clinical approach for the treatment of type 1 diabetes (T1D), was investigated using a mathematical model of T1D in the female nonobese diabetic (NOD) mouse. Analyses of model simulation results indicate that, in addition to the known direct effects of anti-CD3 antibody on T lymphocytes, two additional mechanisms are required for sustained disease remission: (a) rapid regrowth of healthy beta cells following clearance of islet inflammation and (b) enhanced regulatory T cell activity and/or phenotypic changes in antigen presenting cells (APCs) that promote a stable regulatory environment in the pancreas.

A comprehensive review of interventions in the NOD mouse and implications for translation.

Type 1 diabetes (T1D) animal models such as the nonobese diabetic (NOD) mouse have improved our understanding of disease pathophysiology, but many candidate therapeutics identified therein have failed to prevent/cure human disease. We have performed a comprehensive evaluation of disease-modifying agents tested in the NOD mouse based on treatment timing, duration, study length, and efficacy. Interestingly, some popular tenets regarding NOD interventions were not confirmed: all treatments do not prevent disease, treatment dose and timing strongly influence efficacy, and several therapies have successfully treated overtly diabetic mice. The analysis provides a unique perspective on NOD interventions and suggests that the response of this model to therapeutic interventions can be a useful predictor of the human response as long as careful consideration is given to treatment dose, timing, and protocols; more thorough investigation of these parameters should improve clinical translation.

CD8+ T cell tolerance in nonobese diabetic mice is restored by insulin-dependent diabetes resistance alleles.

Although candidate genes controlling autoimmune disease can now be identified, a major challenge that remains is defining the resulting cellular events mediated by each locus. In the current study we have used NOD-InsHA transgenic mice that express the influenza hemagglutinin (HA) as an islet Ag to compare the fate of HA-specific CD8+ T cells in diabetes susceptible NOD-InsHA mice with that observed in diabetes-resistant congenic mice having protective alleles at insulin-dependent diabetes (Idd) 3, Idd5.1, and Idd5.2 (Idd3/5 strain) or at Idd9.1, Idd9.2, and Idd9.3 (Idd9 strain). We demonstrate that protection from diabetes in each case is correlated with functional tolerance of endogenous islet-specific CD8+ T cells. However, by following the fate of naive, CFSE-labeled, islet Ag-specific CD8+ (HA-specific clone-4) or CD4+ (BDC2.5) T cells, we observed that tolerance is achieved differently in each protected strain. In Idd3/5 mice, tolerance occurs during the initial activation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes where CD25+ regulatory T cells (Tregs) effectively prevent their accumulation. In contrast, resistance alleles in Idd9 mice do not prevent the accumulation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes, indicating that tolerance occurs at a later checkpoint. These results underscore the variety of ways that autoimmunity can be prevented and identify the elimination of islet-specific CD8+ T cells as a common indicator of high-level protection.

Memory CD8(+) T cells undergo peripheral tolerance.

Memory T cells differ from naive T cells in that they respond more rapidly and in greater numbers. In addition, memory T cells are generally believed to be less susceptible to tolerance induction than naive T cells. In this study, we show that this is not the case. Using two different methods of tolerance induction, peptide-induced tolerance and crosstolerance, we present evidence that memory CD8(+) T cells are as susceptible to tolerance as naive cells. These results have a direct impact on manipulating T cell responses to self-antigens in order to improve immunotherapy of cancer and autoimmune diseases.