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.

     

Human Immunoglobulin 10 % with Recombinant Human Hyaluronidase: Replacement Therapy in Patients with Primary Immunodeficiency Disorders

Human immunoglobulin is an established replacement therapy for patients with primary immunodeficiency disorders (PIDs). Recombinant human hyaluronidase (rHuPH20) is a spreading factor that temporarily digests hyaluronan in the skin interstitium enabling large volumes of fluid or drug solutions to be infused and absorbed subcutaneously. HyQvia^® (IGHy) is a new combination product whereby rHuPH20 is injected subcutaneously, followed by human immunoglobulin 10 % infused through the same needle. Thus, IGHy can be administered at a reduced frequency compared with non-facilitated subcutaneous injection of human immunoglobulin, and with a lower frequency of infusion reactions than with intravenous administration. Home-based administration of IGHy is also feasible for adequately trained patients. IGHy was compared with intravenous human immunoglobulin 10 % in a non-randomized, open-label, phase 3 study in patients aged ≥2 years with PIDs who were receiving human immunoglobulin replacement therapy (n = 87). In this study, trough IgG concentrations, acute serious bacterial infection rates (primary endpoint) and occurrences of adverse events during the IGHy treatment period were generally similar to those observed during an intravenous treatment period. IGHy was associated with a numerically lower rate of systemic adverse events and a numerically higher rate of localized adverse events than those observed with intravenous treatment. Compared with intravenous administration, IGHy was administered at a significantly higher maximum flow rate and at a similar frequency. Most patients preferred IGHy over intravenous administration. IGHy offers a new method for subcutaneous delivery of human immunoglobulin replacement therapy in patients with PIDs.     

Cholinergic Treatment of Alzheimer’s Disease and Its Influence on Health and the Quality of Life of Carers

The efficacy and safety of four-month courses of rivastigmine and changes in measures of carer burden were studied in a non-randomized group of 25 patients with Alzheimer’s disease (AD). All patients received p.o. rivastigmine and 22 patients received antipsychotic therapy along with rivastigmine on admission. Treatment was continued for 16 weeks (12 weeks in hospital and four weeks in out-patient conditions). These studies showed that the use of rivastigmine in AD patients with behavioral and psychotic disorders at the stage of moderately severe dementia not only improved the patients’ cognitive functions, but also had positive effects in terms of decreasing psychotic and behavioral disorders. Inclusion of rivastigmine in the complex treatment of AD patients led to significant decreases in the need for psychotherapeutic agents, and in some patients to complete withdrawal of all antipsychotics. It is extremely important to emphasize that the use of rivastigmine in patients with moderately severe AD and behavioral disorders led to significant (up to 30%) decreases in the time spent on the care and supervision of the patients, along with decreases in the level of stress and improvements in the health of carers, indicating increases in the quality of life of both patients and their families.     

Efficacy,Safety, and Pharmacokinetics of a New 10 % Liquid Intravenous Immunoglobulin Containing High Titer Neutralizing Antibody to RSV and Other Respiratory Viruses in Subjects with Primary Immunodeficiency Disease

Purpose

Immune globulins for IgG supplementation have been produced for over 35 years with essentially no differentiating features regarding their specific antibody composition. Furthermore, the compositions of plasma donor pools used for IG manufacturing are not standardized. While all immune globulin products meet the specifications set by the US FDA for antibodies to pathogens like measles and polio, they have variable levels of antibodies to other important viruses and infectious pathogens, particularly respiratory syncytial virus (RSV).

Methods

An IVIG was developed that satisfies the requirements for treating patients with primary immune deficiency disease (PIDD) and also has standardized elevated levels of RSV neutralizing antibodies (RI-002). Plasma donors who have naturally occurring high circulating levels of neutralizing anti-RSV antibody were selected as the source for manufacturing IVIG to treat patients with PIDD to prevent serious bacterial infections. While the introduction of the monoclonal antibody Palivizumab has had a dramatic impact in diminishing the burden of RSV disease in the pediatric population, it does not meet the standards for replacing the deficient immune compartments of patients with PIDD.

Results

Fifty-nine patients with PIDD at 9 different sites across the US were enrolled in this study and received regular infusions of RI-002 over the course of 1 year.

Conclusions

There were zero serious bacterial infections, thus meeting the primary endpoint for this trial. The secondary endpoints including days missed from work due to infection, unscheduled visits to the physician, and days of hospitalization due to infection compared favorably to published reports of other IVIG products.

     

Efficacy, Safety and Pharmacokinetics of a Novel Subcutaneous Immunoglobulin, Evogam?, in Primary Immunodeficiency

This phase III, open-label, multi-centre study investigated the efficacy, safety, pharmacokinetics and quality of life impact of Evogam(?), a new chromatographically fractionated 16% subcutaneous immunoglobulin, utilising a 1:1 dose transition ratio from previous immunoglobulin therapy. Thirty-five previously treated patients with primary immunodeficiency received weekly Evogam over 36?weeks. Primary endpoints were rate of serious bacterial infections (SBIs) and steady-state serum immunoglobulin G (IgG) trough concentrations. No SBIs were reported during the study. Evogam produced significantly higher mean trough IgG concentrations with 1:1 dose conversion compared to previous immunoglobulin treatment (8.94 versus 8.27?g/L, p?=?0.0063). Evogam was efficacious in the prevention of infections and maintenance of trough levels using a 1:1 dose conversion. It was well tolerated with no withdrawals due to adverse events and was preferred to IVIg by the majority of patients.     

Do Flexible Goal Adjustment and Acceptance Help Preserve Quality of Life in Patients with Multiple Sclerosis?

Background

Goal regulation strategies such as flexible goal adjustment and acceptance are believed to be protective factors in persons with chronic illness, but research on their relative contributions to quality of life in multiple sclerosis (MS) is lacking.

Purpose

We aimed to test the idea that acceptance and flexible goal adjustment (in contrast to tenacious goal pursuit) may help preserve the quality of life in persons with MS.

Method

A sample of 117 patients with MS was recruited. They completed questionnaires measuring quality of life (physical functioning, psychological distress), acceptance, flexible goal adjustment, and tenacious goal pursuit.

Results

Acceptance significantly accounted for variance in all three indexes of quality of life, beyond the effects of demographic and illness characteristics. The role of goal regulation style was less clear. Flexible goal adjustment significantly accounted for psychological well-being only. Surprisingly, tenacious goal pursuit predicted better psychological functioning and less psychological distress. No support was found for the hypothesis that acceptance and flexible goal adjustment would moderate the relation between illness severity and quality of life.

Conclusion

The findings suggest the potential importance of acceptance in understanding MS patients’ quality of life, although its hypothesized protective function could not be confirmed. Further conceptual work on acceptance and goal regulation style is needed, as well as prospective work investigating their causal status.

     

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.     

Pre-Existing Diabetes in Early Stage Breast Cancer Patients is Associated with Lack of Improvement in Quality of Life 2 Years After Diagnosis

Purpose

Type 2 diabetes is a common comorbidity among breast cancer survivors. Our aim was to assess the association between diabetes and quality of life (QOL) in newly diagnosed early stage (0-IIA) breast cancer patients over a 2-year follow-up.

Methods

We used data from a longitudinal study of 549 breast cancer patients, aged ≥40 years. During four telephone interviews administered 4–6 weeks and 6, 12, and 24 months after definitive surgical treatment, we measured QOL using the Functional Assessment of Cancer Therapy-Breast (FACT-B) scale; higher scores indicate better QOL. Repeated measures analysis of variance was used to test the change over time in total FACT-B and each of the five subscales (physical, social, emotional and functional well-being, and breast cancer concerns), comparing patients with and without diabetes at baseline.

Results

After adjusting for covariates (age, race, body mass index, education, marital status, cancer staging, and surgical side effects), patients with (vs. without) diabetes reported lower QOL over time on the total FACT-B (least-squares mean [standard error] 106.2 [2.1] vs. 112.0 [1.1]; p?=?0.0038) and on physical, social, emotional, and functional well-being subscales (each p?<?0.05). Over the 2-year follow-up, QOL improved significantly for the emotional well-being (p?<?0.0001) and breast cancer concern subscales (p?=?0.0282) among patients without diabetes, but not among patients with diabetes.

Conclusion

Early stage breast cancer patients with diabetes may need additional care considerations to improve QOL.

     

Dynamics of Cognitive Impairments in Patients with Parkinson’s Disease Receiving L-DOPA Treatment

Neuroscience and Behavioral Physiology - Objectives. To assess the dynamics of cognitive impairment (CI) in patients with Parkinson’s disease (PD) during L-DOPA treatment. Materials and...     

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.     

Quality of Life in Women with Localised Breast Cancer or Malignant Melanoma 2 Years After Initial Treatment: a Comparison

Background

Two thirds of female breast cancer patients and more than 80 % of malignant melanoma patients are diagnosed with localised disease and good prognosis with a 5-year relative survival of more than 90 % in Germany.

Purpose

This study was conducted to present quality of life (QoL) data from a German population-based cohort of female breast cancer and melanoma patients without recurrence for approximately 2 years after initial diagnosis.

Methods

In 2003–2004, patients with localised breast cancer and melanoma were recruited from the Munich Cancer Registry (Upper Bavaria, Germany) to answer QoL questionnaires. Differences between breast cancer and melanoma patients were investigated with regard to age and aspects of communication with their medical caregivers.

Results

One thousand three hundred and four breast cancer and 348 melanoma patients were included. Breast cancer patients were about 7 years older and had significantly lower QoL and higher symptom scores than melanoma patients. Communication needs were generally similar in both groups; however, breast cancer patients experienced more empathy from their medical caregivers. In breast cancer patients, communication was an independent factor for all QoL functioning scores.

Conclusions

Even when faced with a similarly good prognosis, breast cancer patients have a worse QoL than melanoma patients 2 years after diagnosis. An explanation may be more distinctive surgery and systemic therapy, older patients with comorbidities and misunderstood risk communication in breast cancer patients that may stoke anxiety and fears. Further reasons could be unceasing public discussion about breast cancer and its instrumentalisation for political purposes.     

Autoimmune and Inflammatory Manifestations in 247 Patients with Primary Immunodeficiency—a Report from the Slovenian National Registry

An abnormal regulation of immune responses leads to autoimmune and inflammatory manifestations in patients with primary immunodeficiencies (PIDs). The objective of our study was to evaluate the frequency of non-infectious and non-malignant manifestations in a large cohort of patients included in the Slovenian national PID registry and to assess the time of manifestation onset with respect to the time of PID diagnosis. Medical records of registered patients were reviewed. Data on autoimmunity, lymphoproliferation, autoinflammation, allergies, PID diagnosis, and underlying genetic defects were collected and analyzed. The time of each manifestation onset was determined and compared with the time of PID diagnosis. As of May 2015, 247 patients with 50 different PIDs were registered in the Slovenian national PID registry (147 males, 100 females; mean age 20 years). Mean disease duration was 14 years; 78 % of patients were younger than 18 years; and 22 % of patients were adults. Diagnosis of PID was genetically confirmed in 51 % of patients. Non-infectious and non-malignant manifestations were present in 69/235 (29 %) patients, including autoimmune manifestations in 52/235 (22 %), lymphoproliferative/granulomatous in 28/235 (12 %), autoinflammatory in 12/247 (5 %), and allergic manifestations in 10/235 (4 %) of all registered patients. Autoimmune manifestations were present in all patients whose PIDs were classified as diseases of immune dysregulation, 47 % of patients with chronic granulomatous disease, and 38 % of patients with predominantly antibody immune deficiencies. A high prevalence of non-infectious and non-malignant manifestations among patients in the Slovenian national PID registry suggests common genetic factors of autoimmunity, inflammation, and immunodeficiency. Patients with PID should be routinely screened for autoimmune and inflammatory manifestations at the time of PID diagnosis and during the long-term follow up.     

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.

     

Autoantibodies to β-Amyloid and Neurotransmitters in Patients with Alzheimer's Disease and Senile Dementia of the Alzheimer Type

The content of autoantibodies to -amyloid protein A_1-42, its neurotoxic fragment A_25-35, and neurotransmitters were studied in the blood of patients with presenile Alzheimer's disease and senile dementia of the Alzheimer type. Significant differences in the relative content of autoantibodies to A_1-42 and autoantibodies to biogenic amines were demonstrated. These results can be used for the development of a biochemical method for differential diagnosis of Alzheimer dementias.     

Pharmacokinetics,Safety, and Tolerability of Subcutaneous Immune Globulin Injection (Human), 10 % Caprylate/Chromatography Purified (GAMUNEX®-C) in Pediatric Patients with Primary Immunodeficiency Disease

Purpose

This phase 4, multicenter, open-labeled, single-sequence, crossover study in pediatric patients (ages 2 to 16) with primary immunodeficiency disease (PID) evaluated the pharmacokinetics, safety, and tolerability for subcutaneously (SC) administered 10 % caprylate/chromatography purified human immune globulin injection (IGIV-C, GAMUNEX®) compared with intravenously (IV) administered IGIV-C.

Methods

This study included a screening phase, run-in phase (where required), IV treatment phase, SC treatment phase, and end of study/early termination visit. Eligible patients receiving a stable dose of IGIV-C entered into the IV phase to receive two IV infusions of IGIV-C (200–600 mg/kg per infusion) every 3–4 weeks. The weekly SC dose of IGIV-C was calculated using a conversion factor of 1.37 times the prior IV dose.

Results

Twelve subjects between the ages of 2 and 16 years participated in the clinical study with the median age being 11 years old. The adjusted weekly mean AUC_0-τ,IV was 216,873.7 h*mg/dL for the IV phase versus a mean AUC_0-τ,SC of 230,830.0 h*mg/dL for the SC phase. The mean (range) C _trough was 997.2?(784–1320)?mg/dL in the IV phase and 1325.0?(1077–1690)?mg/dL in the SC phase. During the SC phase, 100.0 % of the patients (n?=?11) experienced treatment-emergent adverse events (TEAEs) that were local infusion reactions and 9 patients (81.8 %) had TEAEs that were non-infusion site reactions. The majority of TEAEs were mild or moderate in severity.

Conclusion

In pediatric patients with PID, SC-administered IGIV-C provides comparable overall serum exposure to total IgG to that produced by IV-administered IGIV-C. We have concluded that weekly SC administration of 10 % IGIV-C based on a dose conversion factor of 1.37 is safe and well-tolerated in pediatric patients with PID.

Trial Registration

ClinicalTrials.gov identifier: NCT01465958. https://clinicaltrials.gov/ct2/show/NCT01465958?term=NCT01465958.&rank=1

     

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.     

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.

     

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

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.