Amendment 1: In Section 1, 3, 5, and 6 the number of patients and number of ED were reduced. In Section 12.5.2 and 18.4, number of pre-planned safety interim analysis was reduced from two to one. In Section 6.2, an inclusion criteria “Immunocompetent, defined as eithercells >200 cells/μl”, was added. In Section 6.4, one withdrawal criteria,“For inhibitor patients – inhibitor treatment failure with N8 treatment”, was removed. In Section 12.1.2, All hypersensitivity reactions reported as MESIs were to be followed up with a hypersensitivityquestionnaire was added under Adverse events of special interest. Several minor inconsistencies /ambiguities, and apparent mistakes were corrected in the protocol.

Amendment 5: In Section 1, 2, the concept of two different phases of the trial, a main phase and an extension phase was introduced. In Section 4.2, secondary endpoints were updated, “The secondary endpoints will be evaluated for the main phase of trial, for the extension phase of trial, and for the combined main and extension phases.” In Section 5.1, trial duration extended from approximately 50 months to 5 years. In Section 5.3.4, treatment schedule for patients who develop inhibitors was changed, “If needed and decided by the Investigator, the initiation of the inhibitor treatment with turoctocog alfa can be delayed for up to 6 months from the time of diagnosis of inhibitor. If the inhibitor disappears (BU <0.6/mL) during the ITI treatment, the patient should resume preventive treatment as recommended in this protocol, following the visit schedule in the extension phase. For patients still with positive inhibitors after 12 months ITI treatment, continued trial participation will be evaluated based on the level of inhibitors.” In Section 6.1, the planned number of patients to be screened (i.e. documented informed consent) was decreased from 75 to 65. In Section 6.4, one withdrawal criteria, “Haemostasis not achievable with turoctocog alfa: The bleed could not be controlled after 48 hours using recommended doses of turoctocog alfa”, was removed. In Section 8.1, visit details were updated including Extension phase visit, EoT visit In Section, 8.2.9, pulse and blood pressure were removed from the list of vital signs assessment. In Section 18.2.4, supportive secondary efficacy and safety endpoints were updated according to the concept of main phase and extension phase.

Amendment 6: In Section 2 and 5.1, Visit 1 and Visit 2 combined to be performed at the same occasion. This was done to minimize the bleeding risks in untreated patients. In Section 6.2, “Immunocompetent, defined as either HIV negative or if HIV positive, CD4+ cells >200 cells/μL” was removed from inclusion criteria since the immune competency was expected to be present in the vast majority of PUP. This criteria was removed so as to avoid having unnecessary criteria. In Section 6.2, inclusion criteria #2 was updated. Patients had to be diagnosed as opposed to be presenting with congenital severe haemophilia A (FVIII ≤1%). • In Section 6.3, Platelet count <50,000 platelets/μL was removed from exclusion criteria. The exclusion criteria “patients with FVIII inhibitor (>0.6 BU) should be excluded from the trial” was removed. Exclusion criterion was updated to “Any history of FVIII inhibitor”. In Section 12.1.2, Inhibitor formation against FVIII was updated to be always considered as MESI. Analysis of haematology to be performed at central lab. However, if an investigator obtains any indication of inhibitor formation by clinical signs or local laboratory results, it should be reported as MESIs.

Amendment 7: In Section 5.1 and 7, the trial duration (from 5 to 7 years) and end-of-trial date were revised. In Section 5.3, the duration and conditions for the treatment of patients with inhibitors were redefined. In Section 6.1, planned number of patients to complete the main phase of the trial was updated. In Section 6.4, below withdrawal criteria were updated to ensure the safety of patients, who do not benefit from inhibitor treatment with turoctocog alfa. * “Inhibitor treatment has not been started within 6 months from the date of confirmation of positive FVIII inhibitor (BU ≥ 0.6/mL) * FVIII inhibitor titre decline from peak level is less than 20% after 12 months of inhibitor treatment * FVIII inhibitor is positive (BU ≥ 0.6/mL) after 24 months of inhibitor treatment. *After completed inhibitor treatment (maximum 24 months), preventive treatment as described in the protocol is not resumed/started.” In Section 7, trial schedule was updated including details about LPLV, Planned completion of main and updated clinical trial report protocol exceptions. In Section 8.2.2.2, non-neutralising antibodies were defined. In Section 8.3.1, definition of bleeds, severe bleed, and re-bleed were defined. In Section 12.1, definitions of serious adverse events were re-defined, final outcome of an AE and MESI were updated. The possibility to further investigate immunogenicity of turoctocog alfa e.g. binding antibody assessment and HLA genotyping was introduced.

Amendment 9: In Section 7, recruitment period was prolonged to ensure possibility of recruiting Chinese patients as the clinical trial application (CTA) in China was delayed In Section 12.5.2, timing of interim analysis changed to ensure timely interim analysis independent of number of inhibitor patients Number of planned sites increased to fulfil the number of planned recruited patients. Exclusion criteria “Preventive treatment not initiated at age of 24 months” was added In Section 8.2.6, a withdrawal criteria about Lupus Anticoagulant test – (preventive treatment not initiated at age 24 months), long-term retention of blood samples, a new preventive treatment (2x weekly), monitoring visits every 12 weeks – was added. This was done to align with other PUP trials in aemophilia and to ensure better evaluation of inhibitor patients Twice weekly dosing option was introduced. This was done since the gap from once weekly to 3 times weekly infusion of preventive treatment was too big. Sites requested twice weekly frequency to avoid overdosing of patients. Definition of ‘disease-related’ bleeding was changed from being AE to not AE. This was done to align with other guardian protocols and Global Safeties current definition of disease related bleedings In Section, 5.3.2, Guide for dosing in bleeding episodes was added on request of sites. In Section 25, methods of retention of blood samples were defined.

Amendment 10: In Section 7, planned duration of recruitment was increased from 39 to 45 months. Planned dates for last patient first visit (LPFV) and LPLV were also updated. Minor inconsistencies, ambiguities and typographical errors were corrected.