149 DosEmi study protocol Sample size The power calculations are based on the ability to detect a clinically relevant difference between the groups before and after the dose intervention in the proportion of participants without treated bleeding. The treatment centers and study group reached consensus on an expected response of 80% without treated bleeds in both groups before and after dose intervention and a noninferiority margin of 15% (i.e., risk difference) [10]. A required inclusion of 88 participants results from sample size calculations with settings of a noninferiority test, crossover design, binary data, 80% power, one-sided alpha 0.05, noninferiority margin 0.15 and expected response in both groups 0.8 https:// app.sampsize.org.uk. To account for possible drop-out, we will aim for inclusion of 95 participants. The power calculation will be repeated after the first 25 participants have completed 6 months of follow-up after the dose intervention. Recruitment Potential participants, who meet the inclusion criteria, will be informed about the DosEmi study by their treating physician. To allow sufficient time for consideration, the informed consent procedure will be executed after a minimum of one weeks’ delay of the formal invitation and opportunity to ask questions regarding the Informed Consent. Data collection and management All study data will be entered in the Good Clinical Practice (GCP) compliant eCRF system Castor [23]. The medical data will be collected during study visits and monthly contact. The primary source for medical data is the electronic medical record system of the hospitals. Blood samples for routine checks will be measured locally at the laboratories of the hospitals. The blood samples for emicizumab concentration and thrombin generation will be measured centrally in the UMC Utrecht by ISO-certified laboratories. The emicizumab concentration will be measured using a validated liquidchromatography-tandem mass spectrometry (LC-MS/MS) method [24, 25]. Plasma coagulation potential will be measured using thrombin generation tests as a potential read-out for pharmacodynamics. Joint status will be measured by physical examination (Haemophilia Joint Health Score [HJHS]) [26-28], ultrasound (if available, according to the HEAD US score). Health related quality of life (QoL) will be assessed with EQ5D(Y)- 3L [29-31], and PROMIS instruments (Physical Function/mobility and Pain Interference short forms) [32-34]. Assessment of pain during emicizumab administration will be scored with the Visual Analogue Scale (VAS). Sports participation (type, duration, frequency) will be assessed with Modifiable Activities Questionnaire (MAQ) [35, 36]. These QoLquestionnaires (i.e., total of 34 questions per visit) will be sent out electronically via Castor. A data management plan (DMP) is generated to describe data collection, handling, storage and back-up, analysis, archiving, and sharing. Participants will be assigned a unique study number, stored according to GCP requirements. All data will be reported at group level. 8
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