Amendment 1: • Safety laboratory: clarification regarding the timing of safety laboratory testing. • ITI patient follow-up: clarification regarding baseline FVIII inhibitor level determination, recovery time-points, and half-life evaluation. One hour time-point was found to be redundant and was deleted in the schedule table. • Definition/classification of haemorrhages: clarification regarding specification of haemorrhage classification. • Washout period specification: clarification regarding washout prior to follow-up visits. • Adverse events: Correction of safety assessments, adding that AEs and SAEs were to be monitored and recorded throughout the study. • Classification of ADRs: Addressed request asking to further specify the definition regarding expected ADRs. • Specification of blood volume limits: Addressed request asking to further specify the definition regarding the blood volume limits for sampling in neonates. • Definition of PP population: clarification regarding definition of PP population.

Amendment 2: • IMP vial handling: general clarification. • Adaptation of ITI: adaption to comply with international ITI target criteria. • Overall efficacy assessment: clarification regarding the overall efficacy assessment to be done by the surgeon and haematologist together. • Safety laboratory parameter time points: correction of the time points for testing of safety laboratory parameters. • Home treatment with IMP: clarification that IMP for home use would be provided in cooling boxes, if appropriate. • Follow-up visits: clarification regarding timing of the follow-up visits. • Measurement of vital signs after IMP treatment at study site: changes were made to the schedule for measuring vital signs, allowing some flexibility for parents/patients in terms of avoiding unnecessary waiting times at the study site after IMP administration. • RNA Expression Analysis: further specification of the time point of RNA expression analysis was added. • Epitope mapping during ITI follow-up: the time point of epitope mapping analysis was added. • Administration of IMP at home: it was clarified that nurses could also administer IMP at home. • Efficacy assessment specification: A clarification/correction was implemented specifying that the post-operative efficacy assessment was performed by the haematologist only. • Serious adverse event (SAE) reporting: additional reporting line was added. • Epitope mapping – blood collection volume and time-points: additional specifications and corrections were made in connection with the change of the central laboratory responsible for Epitope mapping. • Laboratory change: the central laboratory for Epitope mapping was changed.

Amendment 3: • Study duration: study duration was updated • Dose recommendation for prophylactic/on-demand/surgical prophylactic treatment: the dose recommendations were adapted to those from the approved SmPC for the marketed product (Nuwiq). • Statistical methods and sample size: the first of 2 interim analyses was cancelled since this was not an authority requirement. The second analysis (reported in the interim report) was to be performed as requested by the respective EMA guideline. • Dose rationale for starting dose: the dose recommendations were adapted to those from the approved SmPC for the marketed product (Nuwiq). • Safety and tolerability, and safety lab test specification: additional clarification, including more detailed description of the standard laboratory parameters. • Withdrawal and replacement of patients: a more detailed implementation of the respective EMA guideline with the clarification that patients were not to be replaced only if they had received more than 50 exposures with the IMP. • Dose and dosing schedule: correction made. Dose and dosing schedule: Immune Tolerance Induction: additional clarification, including specification that patients who do not start ITI within 1 year after inhibitor detection are withdrawn from the study. • Study conduct: observations per visit: additional clarification that F8 gene mutation analysis is mandatory but could be performed later in the study. • Data handling and record keeping: documentation of data: general clarification.

Amendment 4: • The study completion timeline was clarified. It was stated that the study would be completed in the 4th quarter 2018 for all patients, except those continuing ITI treatment. • Optional retrospective analysis of blood samples for epitope mapping was introduced in patients who developed an inhibitor against FVIII and started an ITI plus in an inhibitor negative control group. • For health economic parameters, more clarity on information collected from patients’ parents was provided. • More clarity on information collected towards patient demographics during screening visit was provided.