8%; 95% CI: 5.3, AUY-922 in vivo 24.5). However, the inhibitor rate for rFVIII (26.6%; 95% CI: 22.6, 31.0) was significantly greater (P < 0.05) than that for pdVWF/FVIII. Six studies were included in the meta-analysis (Table 2). In four of the six studies, the total inhibitor rate was greater in patients treated with rFVIII than pdVWF/FVIII (17–47% vs. 7–24%). Overall, odds ratios for inhibitor development in the rFVIII versus pdVWF/FVIII group were highly statistically significant: 2.3 (95% CI:

1.7, 3.1; fixed-effects model); and 2.4 (95% CI: 1.7, 3.4; random-effects model). Similarly, patients treated with rFVIII rather than pdVWF/FVIII were 1.9 times more likely to develop HR inhibitors and 2.1 times more likely to develop LR inhibitors (P ≤ 0.004). The overall relative risk of HR DNA-PK inhibitor inhibitors occurring in rFVIII versus pdVWF/FVIII recipients was 1.67 (95% CI: 1.28, 2.18). In conclusion, this systematic review clearly outlines a marked, statistically significant association between rFVIII treatment and inhibitor development. However, limitations of the review include the following: populations in the constituent studies were non-homogeneous regarding issues such as patient ethnicity and treatment regimens employed (e.g. early prophylaxis vs. on-demand treatment); and designs of the component trials were also non-homogeneous regarding issues such as prospective

or retrospective evaluation, frequency and methods of inhibitor testing, study observation Phosphatidylethanolamine N-methyltransferase periods, and the recording of crude versus cumulative incidence rates of inhibitor development. Thus, more data are needed, from multivariate analyses of all known risk factors, to corroborate findings from the current

analysis of inhibitor development during administration of rFVIII or pdVWF/FVIII in PUPs with haemophilia. The ongoing, randomized, prospective Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) will have appropriate statistical power and is expected to clarify the true incidence of inhibitors in PUPs with haemophilia who are given rFVIII or pdVWF/FVIII [17,18]. The SIPPET study was designed to provide further evidence regarding the immunogenicity of recombinant and plasma-derived products. SIPPET is an investigator-initiated, international, interventional study. This pivotal phase IV trial has a multicentre, randomized, open-label, parallel-group design. The primary objective is to assess the immunogenicity of VWF/FVIII and rFVIII concentrates by determining the frequency of inhibitor development in PUPs or minimally blood component-treated patients during the first 50 EDs, or in the first 3 years from enrolment, whichever comes first. Patients included in the trial will be boys aged <6 years with severe haemophilia (FVIII <1%; Table 3), who will be randomized to receive rFVIII (first, second or third generation products without VWF) or pdVWF/FVIII. The target sample size is 300 patients.