Efficacy and Safety of Concizumab Prophylaxis in Adult and Adolescent Patients with Hemophilia A or B Without Inhibitors

The primary objective of this study is to evaluate the efficacy of **concizumab** prophylaxis compared to no prophylaxis (on-demand treatment with factor) in reducing the number of bleeding episodes in adult and adolescent patients with **haemophilia A** and **haemophilia B** without inhibitors. This is clinically relevant as it aims to establish the potential of concizumab as a preventive treatment option, which could significantly improve the quality of life for patients by reducing bleeding episodes.

Secondary objectives include:

• Comparing the effect of concizumab prophylaxis to the patients’ previous prophylaxis treatment in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia A without inhibitors.
• Comparing the effect of concizumab prophylaxis to the patients’ previous prophylaxis treatment in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia B without inhibitors.
• Investigating the safety of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B without inhibitors.
• Investigating the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B without inhibitors.

The clinical trial involves a total of **115 participants** diagnosed with **haemophilia A** without inhibitors and **haemophilia B** without inhibitors. The study population consists exclusively of **male** subjects aged 12 years and older, with a body weight exceeding 25 kg. Participants were selected based on their congenital severe haemophilia A (FVIII < 1%) or moderate/severe haemophilia B (FIX ≤ 2%), and a documented history of treatment with coagulation factor-containing products in the last 24 weeks. The trial does not include a vulnerable population, and no female subjects are involved. The participants' general health status is characterized by their specific haemophilia condition, and no additional lifestyle considerations such as diet or physical activity are specified. The selection criteria ensure that the study focuses on individuals who have a significant history of haemophilia treatment, providing a relevant population for assessing the effects of concizumab prophylaxis compared to on-demand treatment with factor in reducing bleeding episodes.

The clinical trial is designed to evaluate the **efficacy** and safety of **concizumab** prophylaxis in patients with **haemophilia A** or **B** without inhibitors. This is a randomized, double-blind, controlled trial with a primary objective to compare the effect of concizumab prophylaxis to no prophylaxis in reducing the number of bleeding episodes in adult and adolescent patients. The trial is expected to last until June 2026, with participant recruitment having commenced in November 2019. The trial involves a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, body weight, and previous treatment history. Participants must be male, aged 12 years or older, with a body weight greater than 25 kg, and have a documented history of treatment with coagulation factor products.

Following the screening, eligible participants will be randomized into different arms, with some receiving concizumab and others receiving on-demand treatment. The trial will include follow-up visits to monitor the number of treated spontaneous and traumatic bleeding episodes, as well as any adverse events such as thromboembolic events, hypersensitivity reactions, and injection site reactions. The end-of-study visit will conclude the trial, assessing the overall outcomes and safety of the treatment. Participants are expected to be involved for a minimum of 32 weeks, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial employs a subcutaneous route of administration using a prefilled pen-injector, specifically the PDS290 pen-injector, for the delivery of concizumab. The trial is not classified as a low-intervention study and is conducted in accordance with regulatory guidelines to ensure the safety and well-being of participants.

The clinical trial involves the administration of **Concizumab**, a **solution for injection** developed by Novo Nordisk A/S. The trial utilizes two formulations of Concizumab: Concizumab C 100 mg/mL PDS290 and Concizumab C 40 mg/mL PDS290. Both formulations are administered subcutaneously using the PDS290 pen-injector, a prefilled device designed for this purpose. The active substance, Concizumab, is a protein-based therapeutic agent. The trial aims to evaluate the efficacy and safety of Concizumab prophylaxis in patients with **haemophilia A** or **B** without inhibitors.

Concizumab C 100 mg/mL PDS290 is provided as a solution for injection, with a concentration of 100 mg/mL. The administration is performed subcutaneously using the FlexTouch® Pen Injector (PDS290). The dosing schedule is determined based on the trial protocol, with a maximum treatment period of 289 days. Participant compliance is monitored throughout the trial to ensure adherence to the dosing regimen.

Concizumab C 40 mg/mL PDS290 is similarly provided as a solution for injection, with a concentration of 40 mg/mL. It is also administered subcutaneously using the same PDS290 pen-injector. The dosing and administration follow the same guidelines as the 100 mg/mL formulation, with a focus on maintaining participant compliance and monitoring throughout the trial duration.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The primary objective is to compare the effect of Concizumab prophylaxis to no prophylaxis, specifically on-demand treatment with factor, in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia A or B without inhibitors.

The efficacy of the clinical trial evaluating **Concizumab** prophylaxis in patients with hemophilia A or B without inhibitors will be assessed through several primary and secondary endpoints. The primary endpoint focuses on the number of treated spontaneous and traumatic bleeding episodes. For patients with hemophilia A and B without inhibitors, the assessment will be conducted in two arms: on-demand treatment (arm 1) and Concizumab treatment (arm 2). The on-demand arm will be evaluated from randomization after a pause until the start of Concizumab treatment, while the Concizumab arm will be assessed from the start of the new dosing regimen up to the confirmatory analyses cut-off, which is at least 32 weeks.

Secondary endpoints include the number of treated spontaneous and traumatic bleeding episodes for patients who have been on stable prophylaxis for at least 24 weeks in previous studies. Additional secondary endpoints involve the number of treated spontaneous bleeding episodes, joint bleeds, and target joint bleeds, as well as the number of thromboembolic events, hypersensitivity reactions, injection site reactions, and the presence of antibodies to Concizumab. Pharmacokinetic parameters such as pre-dose (trough) plasma concentration, thrombin peak, free TFPI concentration, maximum plasma concentration (Cmax), and area under the plasma concentration-time curve (AUC) will also be measured at specific time points, particularly at week 24 after the restart of treatment.