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Background, objectives and methods Increased intraperitoneal volume (IIPV) can occur during automated peritoneal dialysis (APD). The contribution of factors such as cycler programming and patient/user actions to IIPV has not been previously explored. The relationship between IIPV and cycler programming, patient/user actions, and ultra-filtration over a two-year period was investigated using US data from Baxter cyclers. Drain/fill volume ratios of > 1.6 to ≤ 2.0 and > 2.0 were defined as Level I and Level II IIPV events, respectively. Results Level I IIPV events occurred in 2.39% of standard and 4.73% of small fill volume therapies, while Level II IIPV events occurred in 0.26% and 1.33% of therapies, respectively. IIPV events occurred significantly more often in association with tidal peritoneal dialysis (PD) compared to non-tidal PD therapies. In tidal therapies, IIPV events were primarily related to suboptimal programming of total ultrafiltration volume. Factors that increased the odds of IIPV events during standard therapies included programming the initial drain volume target to < 70% of the last fill, and setting minimum drain volumes to < 85% of the fill volume. Bypass of initial drain by patients/users was also associated with a significant increase in the odds of IIPV events in non-tidal, but not tidal PD. An increase in the odds for IIPV was also seen for standard therapies within the highest (> 1,245 mL) versus the lowest (< 427 mL) quartile of ultrafiltration. Similar trends were seen in small fill volume therapies. Clinical presentations associated with IIPV events were not assessed. Conclusions IIPV events are more frequent in tidal and small fill volume therapies. The greatest potential for IIPV occurred when the total ultrafiltration was set too low for the patient's UF requirements during tidal therapy. Patient/user bypass of drains without reaching the target drain volume contributes significantly to IIPV events in non-tidal PD therapies. Poorly functioning PD catheters may be central to the cycler programming and patient/user actions that lead to IIPV.

A prospective, non-interventional Post-Authorization Safety Surveillance (PASS) program was initiated in 2004 to document ADVATE safety and efficacy in routine clinical practice. More than 900 subjects newly prescribed ADVATE have been enrolled in the US, EU and Japan alone. Herein, we present final US and interim EU results comprising 506 treated subjects, 451 of which have completed the 1-year observation period and 20 ongoing. Age cohorts were as follows: 27 neonates/infants (0-<2 years), 128 children (2-<12 years), 54 adolescents (12-<16 years), and 285 adults (≥16 years); 12 with age unreported. At study entry, 61 patients were considered previously untreated (PUP) or minimally treated (MTPs) defined as ≤50 previous exposure days [EDs]); 437 subjects were considered previously treated patients (PTPs) (>50 previous EDs). Eight subjects had unknown exposure history. Twenty-nine PUPs/MTPs reported exact exposure history prior to ADVATE: 5 reported 0 ED; 7 reported 1 to 3 EDs; and 17 reported 4 to 50 EDs. Most study subjects had FVIII ≤2%; 46 of which were PUPs/MTPs and 389 were PTPs. Among PTPs with FVIII ≤2%, 331 had no known history of inhibitor; 58 reported having a history of inhibitor prior to receiving ADVATE. At enrollment, 58% of subjects were prescribed prophylaxis, while 42% were treated on-demand. A total of 4848 bleeds in 343 subjects were treated. The on-demand efficacy was rated only as excellent/good in 94% of subjects. Subjects who were prescribed ADVATE prophylaxis (N=291) received a mean of 3 infusions per week at 29 IU/kg/ infusion. The median annual bleed rate on prophylaxis was 2.4 bleeds per year. Prophylactic efficacy assessments were provided for 268 subjects; 92% received only excellent/good ratings. Similar efficacy results were seen for the various populations with or without history of inhibitor. No unusual or unexpected AEs were seen in the study. One de novo, low-titer (1.4 BU), transient inhibitor was reported in 331 PTPs with FVIII ≤2% and no prior inhibitor history, providing a de novo inhibitor incidence estimate of 0.3% (95% CI, 0.01% – 1.67%). Two recurrent, low-titer inhibitors (≤1.5 BU) were reported in PTPs with FVIII ≤2%. One de novo, high-titer and 1 de novo, low-titer inhibitor were reported in PTPs with FVIII >2%. Two high-titer inhibitors were reported among 61 PUPs/MTPs. Other SAEs included 1 headache, 2 allergic reactions, 1 ineffective drug response in a subject with inhibitor and ITI history, and 1 hemarthrosis secondary to trauma. Results from the US and EU PASS registries validate the ADVATE safety and efficacy profile in the general hemophilia A population, in real-world clinical settings. Consistent with the formal clinical study findings ADVATE continues to demonstrate low risk for inhibitor development in PTPs.

ADVATE rAHF-PFM was licensed by the FDA in 2003 and the EMEA in 2004 based on studies of previously treated patients (PTPs) with FVIII levels ≤2%. Subsequent to licensure, a PASS program was launched to document rAHF-PFM experience during the first year of routine therapy in subjects with FVIII baseline levels ≤5%, irrespective of prior FVIII exposure or inhibitor history. As of May 25, 2007, a total of 537 subjects (519 male, 2 female, 16 unreported) were enrolled. Of these 537 subjects, 67 were previously untreated or minimally treated patients (PUPs/MTPs) (≤50 exposure days [EDs]), 444 PTPs (>50 EDs), and 26 subjects had an unknown prior exposure status at study entry. Furthermore, 451 had FVIII ≤2%, 62 FVIII >2% to ≤5%, 5 FVIII >5%, 19 unreported. At enrollment, 421 reported switching from recombinant FVIII therapies (343 first generation FL-rFVIII, 38 second generation FL-rFVIII, and 12 BDD-rFVIII), and 76 from plasma-derived-FVIII (34 VWF-containing pdFVIII). Sixty-four subjects had a history of an inhibitor; 33 underwent immune tolerance induction (ITI). Age cohorts were as follows: 0–2 years (n=29), 2–16 years (n=184), and ≥16 years (n=297); 27 were unreported. A total of 417 subjects completed the one-year observation period; 42 withdrew. Twenty AEs were judged at least possibly related to rAHF-PFM; 11 (mostly inhibitors) were rated as serious. Among 387 PTPs with baseline FVIII ≤2%, 2 recurrent, low-titer (1.4 BU and 1.5 BU) and 1 de novo, low-titer (1.4 BU) inhibitors were reported, providing an interim inhibitor risk estimate of 0.78% (95% CI: 0.16–2.25%). In the remaining PTPs, 1 de novo, high-titer (23 BU) inhibitor was reported in a 60-year-old man (FVIII >5%) following surgery, and 1 de novo, low-titer (4 BU) inhibitor, which disappeared 12 months later, developed in a 4-year-old boy (baseline FVIII=5%). Two high-titer inhibitors were reported in PUPs; 1 successfully eradicated with 5 weeks of ITI using rAHF-PFM (100 IU/kg QD). Other related serious AEs included 2 allergic reactions, 1 ineffective drug response in a subject with an inhibitor and ITI history, and 1 hemarthrosis secondary to trauma. Overall, 2771 new bleeds were recorded. Annual bleed rates were 4.3 and 8.3 among subjects on prophylactic and on-demand therapy, respectively. Of 259 subjects with physician-rated prophylaxis efficacy, 91% had only excellent/good ratings. Of 369 subjects with physician-rated bleed treatment efficacy, 94% had only excellent/good ratings. Ratings were comparable among subjects with an inhibitor history. Interim PASS results indicate rAHF-PFM is safe and effective in the management of hemophilia A patients, including those typically excluded from controlled clinical trials.