145 DosEmi study protocol Figure 1. DosEmi study design. A schematic summary of the study design is shown in Figure 1 and in more detail in Supplementary Figure 1. The different phases depicted are a retrospective Clinical Phase, and a total prospective study duration of 18 months, which includes 6 months of bleeding assessment on conventional dosing, 6 months of PK-guided dosing and 6 months of dose continuation. The first participant was enrolled in September 2022 and total inclusions with sufficient follow-up time are expected to be reached in 2026. The study is investigator-driven with the UMC Utrecht as study sponsor. The UMC Utrecht acts as coordinating center and participants will be recruited from all Dutch haemophilia treatment centers, which are located in Amsterdam, Den Haag, Groningen, Leiden, Maastricht, Rotterdam, Utrecht, Nijmegen, and Eindhoven. All sites were involved in the design of the study and have personnel with the expertise to assess bleeds, examine joint health, assist in questionnaires and perform clinical and laboratory monitoring. Day to day activities of the study are performed by the principal investigator (study supervision and medical responsibility), study coordinator (trial registration, coordinates study visits, annual safety reports), study physicians (identify potential participants, obtain informed consent, ensure follow-up according to protocol) and data manager (supports in data capture, safeguards quality of data). The study team of the coordinating center meets weekly. A multidisciplinary study steering committee has been installed, consisting of (but not limited to) haemophilia clinicians, pharmacists, representative from the Dutch Haemophilia Patients Organisation and the SYMPHONY consortium for valued based health care support and PK guidance [21]. Study monitoring will be performed by a professional CRO (Julius Clinical, Zeist, the Netherlands). The monitoring plan is available upon request. Furthermore, the Board of Dutch Haemophilia Treaters (NVHB) and the Steering Committee will act as Scientific Advisory Committee and periodically review study results and safety data. Unblinding and randomization procedures are not 8
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