Safety and efficacy results of simulated post-exposure prophylaxis with human immune globulin (HRIG; KEDRAB) co-administered with active vaccine in healthy subjects: a comparative phase 2/3 trial.

We conducted a clinical trial to assess the safety and putative efficacy of an additional human rabies immune globulin (HRIG; KEDRAB) versus an older product (Comparator, HyperRAB S/D® [Grifols]) and determine whether HRIG interferes with development of endogenous antibodies versus Comparator, when each is given with an active rabies vaccine. This was a prospective, double-blind, single-period, non-inferiority study in which subjects were randomized (1:1) to a single dose (20 IU/kg) of HRIG or Comparator on day 0 and rabies vaccine (RabAvert® [GlaxoSmithKline]; 1 mL of ≥2.5 IU/mL) on days 0, 3, 7, 14, and 28. Anti-rabies antibodies were measured by rapid fluorescent focus inhibition test on day 14, and subjects were followed until day 185. Rabies virus neutralizing antibody (RVNA) titers ≥0.5 IU/mL were considered seroconversion putatively indicative of protection. The non-inferiority criterion was the lower limit of the 90% confidence interval (CI) >-10%, for the between-group difference in the proportion of subjects achieving RVNA ≥0.5 IU/mL. On day 14, 98.3% of 59 subjects in the HRIG group and 100% of 59 in the Comparator group had RVNA ≥0.5 IU/mL (difference between proportions - 1.8%; 90% CI, - 8.2, 3.1; non-inferiority criterion met). One subject in the HRIG group did not meet the seroconversion criteria for anti-rabies antibody, and one subject in the Comparator group showed an anamnestic response, with much higher than expected anti-rabies antibody levels at both baseline and on day 14. Thus, HRIG allows for prophylactic anti-rabies antibody titers and is non-inferior to Comparator, when administered with rabies vaccine.

The impact of CMV prevention on long-term recipient and graft survival in heart transplant recipients: analysis of the Scientific Registry of Transplant Recipients (SRTR) database.

The association between cytomegalovirus immunoglobulin (CMVIG) and long-term clinical outcomes in heart transplantation has not been evaluated using data from large national databases. We examined the association between CMVIG, with and without antivirals, or antivirals alone, and long-term recipient and graft survival in heart transplantation using data from the Scientific Registry of Transplant Recipients. Recipients transplanted between January 1995 and October 2008, ≤80 yr old, of primary, single-organ heart transplants, recorded as receiving CMVIG with or without antivirals (n = 2112), antivirals without CMVIG (n = 12 089), or no prophylaxis (n = 14 661), at hospital discharge, were included. Kaplan-Meier analysis was used to examine death and graft loss at seven yr post-transplantation; Cox proportional hazards regression was used to estimate the adjusted risk of graft loss and death for prophylaxis vs. no prophylaxis. CMVIG use (± other antivirals) was associated with increased recipient (69% vs. 64%, p < 0.001) and graft (67% vs. 63%, p < 0.001) survival. Antivirals alone also demonstrated increased recipient (68% vs. 64%, p < 0.001) and graft survival (66% vs. 63%, p < 0.001). Cox models demonstrated that CMVIG (± other antivirals) was independently associated with decreased risk for death (hazard ratio, HR 0.79, p < 0.001) and graft loss (HR 0.78, p < 0.001) as were antivirals alone (mortality HR: 0.79, p < 0.001; graft loss: HR 0.78, p < 0.001).

Progress in the treatment of bleeding disorders.

The availability of plasma-derived and recombinant coagulation factors has transformed the management of patients with bleeding disorders, such as hemophilia and von Willebrand disease (VWD). However, several important clinical challenges remain that have become the focus of current research in coagulation therapy. Two prospective, non-interventional studies (HyQoL-Europe and HyQoL-Canada) are evaluating the impact of major transitional life events, such as changes in social, work and living situations, on the quality of life of adolescents and young adults with hemophilia A who are treated with the recombinant factor VIII (rFVIII) concentrate Helixate®. A better understanding of the impact of these transitional life events on quality of life may help to develop improved interventions and counseling techniques that minimize the negative effects of these events on patients with bleeding disorders. A new clinical development program has been launched to evaluate the safety and efficacy of the low-volume, highly active, plasma-derived von Willebrand factor (VWF)/FVIII concentrate Biostate®. The program, known as SWIFT (Studies with von Willebrand factor/factor VIII) includes four clinical trials involving adult and pediatric patients with hemophilia A or VWD. Lastly, fusion of human recombinant albumin to recombinant coagulation factor IX (rFIX) has created a new fusion protein (rIX-FP) that retains the biological activity of rFIX and has a more favorable pharmacokinetic profile due to the longer half-life. The use of this novel fusion protein may offer several advantages to patients with hemophilia B: less frequent administration, prolonged protection from bleeding and improved compliance--increasing the likelihood of a positive clinical outcome. These examples of current research endeavors are intended to enhance the treatment experience as well as provide new and improved therapies for patients with bleeding disorders.

Improved quality of life, immunoglobulin G levels, and infection rates in patients with primary immunodeficiency diseases during self-treatment with subcutaneous immunoglobulin G.

OBJECTIVES: Primary immunodeficiency diseases (PIDDs) include a large class of genetically heterogeneous disorders which predispose patients to significant risk of serious and chronic/recurrent infections, as well as reduced quality of life (QoL). Intravenous immunoglobulin (IVIG) therapy improves the well being of PIDD patients; however, the need for venous access and potentially severe side effects frequently require administration in medical facilities. We evaluated the long-term (12-month) experience with home-based self infusions of subcutaneous immune globulin (SCIG) in patients with PIDD on health-related QoL, rates of serious bacterial infections, and all other infections. METHODS: Adults (n = 42) and children (n = 9) with PIDD, previously treated with clinic-based IVIG, were trained to self administer SCIG at home. QoL (SF-36(R) and CHQ-PF50 questionnaires), serious bacterial infections, serum immunoglobulin G (IgG) levels, overall infections, and incidence of adverse events were recorded at predetermined intervals. RESULTS: All patients had improved perceptions of general health (adults P = 0.047, children P = 0.037). Adults also had marked improvement in the bodily pain and vitality assessments, and parents had improved perceptions of personal and family activities. Serum IgG levels were maintained at mean levels 25% higher than previous troughs on IVIG. There were 162 infections overall for an annual rate of 3.42/patient, but only 1 serious bacterial infection was observed (0.03/patient/yr). An average of 4.5 days/yr was missed from work or school per patient. CONCLUSIONS: Home SCIG therapy was safe and led to improved perceptions of general health, higher serum IgG levels, and very low rates of infections and days missed from work/school.

Animal model and clinical evidence indicating low thrombogenic potential of fibrinogen concentrate (Haemocomplettan P).

The objective of this study was to characterize the thrombogenicity of one pasteurized fibrinogen concentrate (Haemocomplettan P) in clinical use for over 20 years. Thrombus formation during venous stasis was assessed in rabbits receiving either 100 or 250 mg/kg Haemocomplettan P. Thrombotic adverse events possibly related to Haemocomplettan P were documented in a long-standing pharmacosurveillance program. A systematic review of thrombotic events in Haemocomplettan P clinical studies was also conducted. There was no evidence of thrombus formation during venous stasis in any Haemocomplettan P-treated animal. The pharmacosurveillance program spanned 22 years, during which a Haemocomplettan P quantity equivalent to more than 250 000 doses of 4 g each was distributed in 21 countries. Nine spontaneous reports of thrombotic adverse events possibly related to Haemocomplettan P were compiled, corresponding to an incidence rate of 3.48 events per 10 treatment episodes (95% confidence interval, 1.59-6.61 events per 10 treatment episodes). In 10 clinical studies involving 298 patients, one patient developed nonfatal venous thrombosis and pulmonary embolism to which fibrinogen concentrate may have contributed. Additionally, four other patients experienced arterial ischemic events that were likely attributable to massive hemorrhage and hypotension rather than fibrinogen replacement. Evidence from an animal model of venous stasis, a comprehensive pharmacosurveillance program, and a systematic review of clinical studies indicates that the thrombogenic potential of fibrinogen concentrate is low.