Nuwiq for Perioperative management Of patients With haemophilia A on Emicizumab Regular prophylaxis study (NuPOWER)

The primary objective of this study is to evaluate the overall **perioperative haemostatic efficacy** of Nuwiq, in combination with ongoing emicizumab prophylaxis, in patients with severe **haemophilia A** undergoing major surgery. This is clinically relevant as it aims to ensure effective management of bleeding during surgical procedures in this patient population, which is critical for reducing perioperative morbidity and improving surgical outcomes.

Secondary objectives include:

• Evaluating intra- and post-operative surgical haemostatic efficacy of Nuwiq, in combination with emicizumab prophylaxis.
• Assessing perioperative coagulation factor VIII (FVIII) plasma levels in patients receiving Nuwiq with emicizumab prophylaxis.
• Evaluating perioperative thrombin generation (TG) in patients receiving Nuwiq with emicizumab prophylaxis.
• Assessing perioperative efficacy of Nuwiq, in combination with emicizumab prophylaxis, using criteria recommended by the World Federation of Hemophilia (WFH).
• Evaluating perioperative safety of Nuwiq in combination with emicizumab prophylaxis.

The clinical trial involves a total of **5 male participants** diagnosed with **severe haemophilia A**, characterized by a factor VIII activity of less than 1%. The study population is composed of individuals who are at least 12 years of age and have a history of treatment with factor VIII products for a minimum of 150 exposure days. Participants are required to be on regular prophylaxis with emicizumab for at least three months prior to undergoing a scheduled major elective surgery that necessitates factor VIII treatment. The selection criteria ensure that participants are not from a vulnerable population, and all have provided freely given written informed consent. The trial does not include female subjects, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection process.

The clinical trial is designed to evaluate the **perioperative haemostatic efficacy** of Nuwiq in combination with ongoing emicizumab prophylaxis in patients with severe **haemophilia A** undergoing major surgery. This study is a phase IV, randomized, double-blind, controlled trial, which is categorized as low intervention due to the use of Nuwiq in accordance with its existing marketing authorization. The trial is expected to commence recruitment on June 1, 2023, and conclude by March 1, 2025, with a maximum treatment period of 30 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as severe haemophilia A with FVIII activity <1%, male patients aged 12 years or older, and a history of at least 150 exposure days to any FVIII product. Following the screening, eligible participants will be enrolled and randomized to receive Nuwiq via **intravenous injection**. The primary endpoint is the overall haemostatic efficacy of Nuwiq, assessed as "success" or "failure" during major surgery. Secondary endpoints include intraoperative and postoperative haemostatic efficacy, perioperative FVIII plasma levels, and the incidence of adverse events, thrombotic events, and FVIII inhibitor formation.

Study visits will include follow-up assessments to monitor the efficacy and safety of the treatment, with specific evaluations of haemostatic efficacy using a 4-point ordinal scale. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted. Participant involvement is expected to last up to 30 days, with conditions for early termination including withdrawal of consent, adverse events, or protocol non-compliance. The trial aims to provide valuable insights into the management of haemophilia A in the context of major surgical procedures.

The clinical trial involves the administration of **Nuwiq**, a recombinant human coagulation factor VIII, known as **simoctocog alfa**. This experimental medication is provided in various dosages, including 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 2500 IU, 3000 IU, and 4000 IU. Each dosage is formulated as a **powder and solvent for solution for injection**. The pharmaceutical form is a **solution for injection**, and the route of administration is **intravenous injection**. The treatment is administered as needed, with a maximum treatment period of 30 days. The medication is not a paediatric formulation and is not classified as an orphan drug. The active substance, simoctocog alfa, is a protein of non-human origin, specifically categorized under the ATC code B02BD02, which corresponds to coagulation factor VIII.

In addition to the experimental treatment, participants will continue their ongoing prophylaxis with **emicizumab**, a standard-of-care therapy for patients with severe **haemophilia A**. Emicizumab is not part of the experimental treatment but is used in combination with Nuwiq to evaluate the overall perioperative haemostatic efficacy. The study does not include a placebo or comparator treatment. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to assess the efficacy of Nuwiq in conjunction with emicizumab during major surgical procedures in patients with severe haemophilia A.

The efficacy of Nuwiq in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the overall haemostatic efficacy, categorized as "success" or "failure," in patients with severe **haemophilia A** who are receiving emicizumab prophylaxis and undergoing major surgery. Secondary endpoints include the assessment of intraoperative and postoperative haemostatic efficacy using a 4-point ordinal scale, perioperative **Factor VIII (FVIII)** plasma levels measured immediately before (≤30 minutes) and after (15-30 minutes) Nuwiq injections, and perioperative haemostatic efficacy assessed using the 4-point scale recommended by the World Federation of Hemophilia (WFH).

Additional secondary endpoints involve the incidence of adverse events (AEs), thrombotic events, and FVIII inhibitor formation. The number of allogeneic blood products transfused, including red blood cells and platelets, will also be recorded. Perioperative thrombin generation (TG) will be measured immediately before (≤30 minutes) and after (15-30 minutes) Nuwiq injections. These assessments will provide a comprehensive evaluation of the haemostatic efficacy of Nuwiq in the specified patient population.