Results of a randomized phase III/IV trial comparing intermittent bolus versus continuous infusion of antihaemophilic factor (recombinant) in adults with severe or moderately severe haemophilia A undergoing major orthopaedic surgery.

INTRODUCTION: In patients with haemophilia A undergoing surgery, factor VIII (FVIII) replacement therapy by continuous infusion (CI) may offer an alternative to bolus infusion (BI). AIM: To compare the perioperative haemostatic efficacy and safety of antihaemophilic factor (recombinant) (ADVATE® ; Baxalta US Inc., a Takeda company, Lexington, MA, USA) CI or BI administration. METHODS: In this multicentre, phase III/IV, controlled study (NCT00357656), 60 previously treated adult patients with severe or moderately severe disease undergoing elective unilateral major orthopaedic surgery (knee replacement, n = 48; hip surgery, n = 4; other, n = 8) requiring drain placement were randomized to receive antihaemophilic factor (recombinant) CI (n = 29) or BI (n = 31) through postoperative day 7. Primary outcome measure was cumulative packed red blood cell (PRBC)/blood volume in the drainage fluid within 24 h after surgery, used to establish non-inferiority of CI to BI. RESULTS: CI:BI ratio of cumulative PRBC volume in the 24-h drainage fluid was 0.92 (p-value <.001 for non-inferiority; 95% confidence interval, 0.82-1.05). Total antihaemophilic factor (recombinant) dose per kg body weight received in the combined trans- and postoperative periods was similar with CI and BI to maintain targeted FVIII levels during/after surgery. Treatment-related adverse events (AEs) were reported in five patients treated by CI (eight events) and five treated by BI (six events), including two serious AEs in each arm. CONCLUSION: CI administration of antihaemophilic factor (recombinant) is a viable alternative to BI in patients with haemophilia A undergoing major orthopaedic surgery, providing comparable efficacy and safety.

Postauthorization safety surveillance study of antihaemophilic factor (recombinant) reconstituted in 2 mL sterile water for injection in children with haemophilia A.

INTRODUCTION: Antihaemophilic factor (recombinant) (rAHF; ADVATE® ) is approved for prophylaxis and treatment of bleeding in children and adults with haemophilia A. Reconstitution in 2 mL sterile water for injection instead of 5 mL allows for a 60% reduction in infusion volume and administration time, but could increase the likelihood of hypersensitivity and infusion-related reactions, especially in children. AIM: To assess local tolerability, safety and effectiveness of rAHF 2 mL during routine clinical practice factor VIII (FVIII) replacement (on-demand and prophylaxis) in children with severe (FVIII < 1%) or moderately severe (FVIII 1%-2%) haemophilia A. METHODS: This was a prospective, non-interventional, postauthorization safety surveillance study (NCT02093741). Eligible patients were previously treated with rAHF and had a negative inhibitor test result during ≤10 exposure days prior to study entry. RESULTS: Of 65 patients enrolled (0-11 years of age), 54 and 11 had severe and moderately severe haemophilia A, respectively; 56 patients received prophylaxis, and 11 had ≤50 exposure days, of which 4 had ≤4 exposure days. No patients reported local hypersensitivity reactions, treatment-related adverse events or developed inhibitors. Investigators rated overall effectiveness of rAHF 2 mL prophylaxis as excellent or good. Ninety-four bleeding events in 34 patients were treated. Haemostatic effectiveness was rated as excellent or good for 75.8% of bleeds; 86.2% of bleeds required 1 or 2 infusions. CONCLUSION: In children with severe/moderately severe haemophilia A, no hypersensitivity reactions were reported with rAHF 2 mL treatment, and the safety and effectiveness are consistent with data previously reported for rAHF 5 mL.

Perioperative haemostasis with full-length, PEGylated, recombinant factor VIII with extended half-life (rurioctocog alfa pegol) in patients with haemophilia A: Final results of a multicentre, single-arm phase III trial.

INTRODUCTION: Rurioctocog alfa pegol (BAX 855, TAK-660) is a PEGylated, full-length, recombinant factor VIII (rFVIII) with extended half-life developed from unmodified rFVIII (antihaemophilic factor [recombinant]). AIM: To determine the perioperative haemostatic efficacy and safety of rurioctocog alfa pegol in male previously treated patients (PTPs) with severe haemophilia A. METHODS: This multicentre, single-arm, phase III study included PTPs who were to undergo major or minor elective or minor emergency surgical, dental or other invasive procedures. Rurioctocog alfa pegol dose and frequency were individualized based on patients' pharmacokinetic profiles for major surgeries and by rurioctocog alfa pegol incremental recovery for minor surgeries. Haemostatic efficacy was assessed using the Global Haemostatic Efficacy Assessment score. RESULTS: Twenty-one patients aged 16-61 years underwent 21 major and five minor surgeries. For all 24 evaluable surgeries, overall haemostatic efficacy was rated as excellent and blood loss comparable to that expected in non-haemophilic patients. No blood transfusions were required intraoperatively but were administered postoperatively for four surgeries in three patients. Five injury-related postoperative bleeding episodes occurred in five patients, of which two required additional rurioctocog alfa pegol treatment. Two non-serious adverse events of mild severity (increased ALT level and headache) were considered possibly related to rurioctocog alfa pegol. There were no deaths or treatment-related serious adverse events. No patients developed inhibitory antibodies to FVIII or persistent IgG- or IgM-binding antibodies to FVIII, PEG-FVIII or PEG. CONCLUSION: Rurioctocog alfa pegol was well tolerated and effective for perioperative use in patients with haemophilia A and showed no signs of immunogenicity.

Safety and tolerability of subcutaneous immunoglobulin 20% in primary immunodeficiency diseases from two continents.

Aim: This pooled analysis evaluated the safety and tolerability of the subcutaneous immunoglobulin 20% product, Ig20Gly, in primary immunodeficiency diseases using data from two Phase II/III studies conducted in North America and Europe. Patients & materials/methods: Patients received Ig20Gly (volumes, ≤60 ml/site; rates, ≤60 ml/h/site). Adverse events (AEs), tolerability and infusion parameters were assessed. Results: Patients (2-83 years; N = 122) received 6676 Ig20Gly infusions. No causally related serious or severe AEs were reported. Thirty-five patients (28.7%) reported 232 causally related local AEs. Twenty-seven patients (22.1%) reported 165 causally related systemic AEs. There was no association between the infusion volume or rate and causally related local AEs. Conclusion: Ig20Gly was well tolerated in a broad population of patients with primary immunodeficiency diseases.

Tolerability of subcutaneous immunoglobulin 20%, Ig20Gly, in pediatric patients with primary immunodeficiencies.

AIM: To assess Ig20Gly tolerability in pediatric patients with primary immunodeficiencies. PATIENTS & METHODS: Infusion parameters and tolerability were analyzed in pediatric patients (aged 2-5 years [n = 6], 6-11 years [n = 22] and 12-17 years [n = 22]) receiving Ig20Gly in two Phase II/III trials. RESULTS: Of 2624 Ig20Gly infusions, >99% did not require any rate reduction, interruption or discontinuation due to adverse events (AEs). Median maximum infusion rates and volumes/site were higher in patients 12-17 years of age (30 ml/h/site; 30 ml/site) versus 6-11 years (20 ml/h/site; 15 ml/site) and 2-5 years (18 ml/h/site; 14 ml/site). Rates of causally related systemic and local AEs (0.009 and 0.063 AEs/infusion) were low. CONCLUSION: Ig20Gly infused at relatively high rates and volumes was well tolerated in children.

Perioperative safety and hemostatic efficacy of Advate® in patients with hemophilia A in a postmarketing surveillance in Japan.

Rurioctocog alfa (recombinant factor VIII: Advate®) is available for the control of bleeding among patients with hemophilia A in Japan. To evaluate the perioperative safety and hemostatic efficacy of Advate®, a postmarketing surveillance was conducted in Japanese patients undergoing surgery in a real-world setting. A total of 74 surgical procedures performed in 58 subjects aged 0-75 years, including three females, were studied. A hemostatic efficacy rating of "excellent" or "good" was reported in 73/74 surgical procedures (98.6%). Perioperative bleeding was successfully controlled by Advate® in five subjects with positive FVIII inhibitors (2.4-9.1 BU/mL). Advate® was administered at higher initial bolus doses (114-385 IU/kg) and at higher rates by subsequent initial continuous infusion (8.3-15 IU/kg/hour) in the five subjects with inhibitor than in the subjects without inhibitor (n = 47; mean initial bolus dose: 53.4 IU/kg; subsequent mean initial continuous infusion: 3.8 IU/kg/h). Adverse drug reactions were reported in 7/74 (9.5%) procedures, two of which were the development of de novo FVIII inhibitors. Overall, the perioperative use of Advate® in a real-world setting was found to be safe and effective among Japanese patients with hemophilia A.

Recombinant human hyaluronidase facilitated subcutaneous immunoglobulin treatment in pediatric patients with primary immunodeficiencies: long-term efficacy, safety and tolerability.

AIM: To assess the long-term efficacy, safety and tolerability of recombinant human hyaluronidase-facilitated subcutaneous infusion of immunoglobulin (Ig) (fSCIG; HYQVIA(®); IGHy) in children aged <18 years. PATIENTS & METHODS: Patients with primary immunodeficiency diseases were included in the studies. IGHy was administered every 3 or 4 weeks. RESULTS: Validated acute serious bacterial infections were reported at 0.08/patient-year (four pneumonia episodes in three patients). No serious adverse drug reaction (ADR) was reported, and rates of local and systemic ADRs were low (0.09/infusion and 0.1/infusion). Infection rates were low (3.02/patient-year) with sustained Ig trough levels (median: 1009 mg/dl). Of 674 IGHy infusions, 97.2% required no change of administration due to ADR, in most (82.5%) with one infusion site. No patient developed neutralizing anti-rHuPH20 antibodies. Postpivotal study, 100% of patients aged <14 years or their caregivers and 85.7% of patients aged 14 to <18 years expressed preference for IGHy compared with Ig administered intravenously or Ig administered subcutaneously. CONCLUSION: These studies, with the longest (maximum: 3.3 years) duration of any reported Ig replacement trials in children with primary immunodeficiency diseases, showed low infection, local and systemic reaction rates along with well-tolerated infusions given in a single site.

Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study.

BACKGROUND: Meningococcal septic shock in children results in high mortality and morbidity, and decreased protein C levels in these patients are associated with a poor outcome. We carried out a randomized, double-blinded, placebo-controlled study by supplying protein C concentrate. This phase 2 study was designed to assess the activation process of protein C and to study the dosing regimen of protein C concentrate in children with purpura fulminans and meningococcal septic shock in the perspective of a possible phase 3 trial. METHODS: Forty children were randomized to receive placebo or protein C concentrate (200 IU/kg, 400 IU/kg, or 600 IU/kg), for a maximum of 7 days. Clinical and laboratory data, including plasma levels of protein C and activated protein C (APC), were collected at various time points. All patients received standard therapy for septic shock, including antibiotics, inotropic/vasoactive drugs, and blood products. RESULTS: Increased APC levels relative to baseline were observed for the 27 of 28 patients treated with protein C concentrate, and the areas under the curve of protein C and APC were correlated with the dosage of protein C concentrate administered. Activation of coagulation, as evidenced by d-dimer levels, as well as the ratio of thrombin vs. APC normalized significantly faster with increasing dosages of protein C concentrate. No adverse reactions related to protein C concentrate were observed. Nine of the 40 (23%) patients died, and five survivors required amputations, with no differences in these rates among the randomized groups. Baseline APC levels were positively correlated with sequential organ failure assessment and pediatric risk of mortality scores and with d-dimers, tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8, plasminogen activator inhibitor-1, TAT complexes, and PAP complexes. CONCLUSIONS: Treatment with protein C concentrate is safe in children with purpura fulminans and meningococcal septic shock and leads to dose-related increases of plasma APC and resolution of coagulation imbalances.

Successful treatment of patients with von Willebrand disease using a high-purity double-virus inactivated factor VIII/von Willebrand factor concentrate (Immunate).

Fourteen patients with different types of von Willebrand disease (vWD) having acute bleeds or elective surgery were treated with Immunate(sound recording copyright sign), a double-virus inactivated factor VIII/von Willebrand factor (FVIII/vWF) concentrate. The concentrate was applied as a bolus or via continuous infusion. FVIII activity (FVIIIc), vWF antigen (vWF:Ag), ristocetin cofactor activity (vWF:RCo), collagen binding activity (vWF:CB), activated partial thromboplastin time (aPTT), and von Willebrand multimers (vW-multimers) were monitored for 48 hours. Pharmacokinetic analyses were performed. The clinical efficacy was rated excellent or good. Bleeding complications occurred in 3 patients due to an additional FXIII deficiency in one patient, to a surgically induced bleed in another patient, and a rather short substitution period in the third patient. There were no serious adverse experiences. One patient showed a phlebitic reaction at the site of venous access after more than 100 hours of continuous infusion, requiring a change to application via bolus.