147 DosEmi study protocol Secondary outcomes The secondary outcomes on bleeds are: - The proportion of patients without treated bleeds in the follow-up periods of 12 months on conventional dosing in comparison to 12 months on individual PK-guided dosing; - The proportion of patients without spontaneous joint- or muscle bleeds in the periods of 6 and 12 months on conventional dosing in comparison to the 6 and 12 months on individual PK-guided dosing respectively; - Annualized Bleed Rates (ABRs) of treated bleeds, including joint bleeds and sports induced bleeds in the periods of 6 and 12 months on conventional dosing in comparison to the 6 and 12 months on individual PK-guided dosing respectively. Other secondary outcomes are: Health Related Quality of Life (HR-QoL), maintenance of stable joint health and sports participation will be compared before and after the dose intervention, reduced pain due to emicizumab injections, the performance of the population PK model, the cost-effectiveness, thrombin generation parameters as pharmacodynamic (PD) biomarkers for emicizumab treatment efficacy. Assessments The study design is shown in Figure 1, Supplementary Figure 1 and the schedule of all assessments over time is presented in Supplementary Table 1. If inclusion criteria are met and informed consent is signed, the retrospective data on bleeds during the six months prior to inclusion will be collected (Clinical Phase [nonstudy, used for inclusion criterion]). Upon inclusion in the DosEmi study, participants will be monitored for a period of six months to prospectively assess bleeds (Bleeding Assessment Phase). During the following phase, participants are categorized into the ‘dose-intervention group’ when plasma emicizumab concentrations at visit 1 are ≥40 µg/mL, or the ‘No Dose Intervention Group’ when emicizumab plasma levels are <40µg/mL. The dose-intervention group undergoes individualized PK-guided dosing of emicizumab at 2-3 weeks after Visit 1 (Dosing Day). The emicizumab concentration is checked again on Visit 2, and if the target concentration was not reached the (optional) Visit 3 is planned to check emicizumab concentration after the second dose adjustment. Participants will be followed for six months after Visit 1 (PK-guided Dosing Phase), after which the participants continue with their PK guided dosing regimen for another six months (Dose Continuation Phase). Thus, a total of 12 prospective months of follow-up on PK-guided dosing regimen per participants are obtained. The No-dose-intervention group includes two groups for observational data collection. Participants with an emicizumab plasma concentration 25-39 µg/mL at Visit 1 will continue on their current dose regimen and will be followed according to the same 8
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