Anouk Donners

150 Chapter 8 Statistical methods All analyses will be performed by within-patient comparisons using paired tests. All participants receiving dose reduction will be included in the statistical analyses, merging data of Cohort 1 and Cohort 2. Primary and secondary outcomes on proportion of bleeds will be analysed with McNemar test one sided p-value threshold 0.05. The treated A(J)BRs (mean and 95% confidence intervals) will be modelled with negative binomial regression. Data from withdrawn participants with at least 1 concentration sample available can be included in the analysis. Treatment adherence will be assessed by the percentage of vials distributed by the hospital pharmacy versus prescribed by physician. The percentage of vials taken will be calculated as: 100 × (total number of vials administered) / (total number of vials prescribed). The percentage of vials taken will be summarized descriptively as quantitative variables. The number and percentage of participants whose treatment compliance is <80% or ≥80% will be summarized. Available data of non-adherent participants will be included in the analysis of bleeding according to emicizumab concentration. Missing data on emicizumab concentrations or bleeding will not be imputed nor analyzed. Safety The collection of AEs will be limited to AEs of special interest (AESI). The AESIs include bleeds (i.e., trauma-related or spontaneous), haemophilia-related events (such as inhibitor development or pain), thromboembolic events (arterial, venous, catheter related and thrombotic microangiopathy [TMA]) and development of neutralizing ADAs. Recording of serious adverse events (SAE) will be restricted to SAEs of special interest (SAESI) as well. The SAESI will be immediately reported to the coordinating investigator and announced to the Medical Ethics Review Committee of the UMC Utrecht. ETHICS AND DISSIMINATION The protocol of the DosEmi Study was approved by the MERC NedMec of the UMC Utrecht (local study registration number NL81112.041.22) on July 2022. Approval by the local MERCs of participating centers is requested/pending. All substantial amendments to the protocol will be notified to the MERC and competent authority. Non-substantial amendments will be recorded and filed by the coordinating investigator. All participants or their guardians will be asked to provide written informed consent to participate in the study. All study procedures will be performed in accordance with the ethical standards of the Declaration of Helsinki (Fortaleza, Brazil, October 2013) and the Medical Research Involving Human Subjects Act (WMO). Results from this study will be analysed and submitted for publication in peer-reviewed international scientific journals and presented at scientific meetings. The coordinating investigator will initiate these scientific activities. There are no restrictions regarding