Efficacy and Safety of Concizumab Prophylaxis in Reducing Bleeding Episodes in Adult and Adolescent Patients with Hemophilia A or B with Inhibitors

The primary objective of this study is to compare the effect of **concizumab** prophylaxis to no prophylaxis (on-demand treatment with bypassing agents) in reducing the number of bleeding episodes in adult and adolescent patients with **haemophilia A** or **B** with inhibitors. This is clinically relevant as it aims to address the significant challenge of managing bleeding episodes in patients with inhibitors, which complicates standard treatment approaches.

Secondary objectives include:

• To compare the patient-reported outcomes (PROs) after treatment with concizumab prophylaxis versus no prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors.
• To investigate the safety of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors.
• To investigate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors.

The clinical trial involves a total of **91 participants** who are exclusively **male** and aged 12 years and older. The study population consists of individuals diagnosed with **haemophilia A (HA) with inhibitors** and **haemophilia B (HB) with inhibitors**. Participants were selected based on specific criteria, including a body weight greater than 25 kg and a documented history of inhibitors with a Bethesda unit (BU) of 0.6 or higher. The trial does not include female subjects, and the participants are not considered a vulnerable population. The health status of the participants is characterized by their need for treatment with bypassing agents within the last 24 weeks prior to screening. Lifestyle factors such as diet and physical activity are not specified in the trial data provided. The selection process ensured that all participants provided informed consent before any trial-related activities commenced.

The clinical trial is designed to evaluate the **efficacy** and safety of **concizumab** prophylaxis in patients with **haemophilia A** or **B** with inhibitors. This is a randomized, double-blind, controlled trial comparing the effect of concizumab prophylaxis to no prophylaxis, specifically on-demand treatment with bypassing agents, in reducing the number of bleeding episodes. The trial is expected to last until December 31, 2025, with recruitment having started on October 21, 2019. The trial involves two arms: one receiving concizumab and the other receiving on-demand treatment. The primary endpoint is the number of treated spontaneous and traumatic bleeding episodes, with secondary endpoints including changes in SF36v2 bodily pain and physical functioning, as well as the number of thromboembolic events and hypersensitivity reactions.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age, body weight, and medical history of inhibitors. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and safety. The end-of-study visit will conclude the trial for each participant, assessing the overall outcomes and any adverse events. The expected length of participant involvement is up to 280 weeks, depending on the treatment arm and individual response to the intervention. Conditions that may lead to early termination from the study include significant adverse reactions or non-compliance with the study protocol.

Participants will receive concizumab via subcutaneous injection using the PDS290 pen-injector, a prefilled device specifically designed for this trial. The trial will ensure that all procedures adhere to ethical standards, with informed consent obtained prior to any trial-related activities. The trial is not classified as a low-intervention study, given its focus on safety and efficacy in a target population for prophylaxis. The trial is conducted under the sponsorship of Novo Nordisk A/S, with concizumab being the investigational medicinal product under evaluation.

The clinical trial involves the administration of **Concizumab**, a **solution for injection** developed by Novo Nordisk A/S. Two formulations of Concizumab are utilized in this study: Concizumab C 40 mg/mL PDS290 and Concizumab C 100 mg/mL PDS290. Both formulations are administered subcutaneously using the PDS290 pen-injector, a prefilled device specifically designed for this purpose. The active substance, Concizumab, is a protein of non-specified origin. The trial does not specify a maximum daily or total dose, but the maximum treatment period is set at 273 days. The dosing schedule is determined based on the participant's weight, with the unit of measurement being milligrams per kilogram (mg/kg).

In addition to the experimental treatment, the study includes a comparator group receiving standard-of-care therapy, which involves on-demand treatment with bypassing agents. This approach is used to evaluate the efficacy of Concizumab prophylaxis in reducing the number of bleeding episodes in patients with **haemophilia A** or **B** with inhibitors. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the protocol. The trial aims to provide a comprehensive assessment of the safety and efficacy of Concizumab as a prophylactic treatment in this patient population.

The efficacy of **concizumab** prophylaxis in patients with **haemophilia A or B** with inhibitors will be assessed by comparing the number of treated spontaneous and traumatic bleeding episodes between two groups: those receiving concizumab prophylaxis and those receiving on-demand treatment with bypassing agents. The primary endpoint is the number of treated bleeding episodes, measured from randomization (week 0) up until the start of concizumab treatment for at least 24 weeks in the on-demand group, and from the start of the new concizumab dosing regimen up until the primary analysis cut-off for at least 32 weeks in the concizumab group.

Secondary endpoints include changes in SF36v2 bodily pain and physical functioning from the start of treatment until week 24, the number of treated spontaneous and traumatic joint bleeds, target joint bleeds, thromboembolic events, hypersensitivity type reactions, injection site reactions, and the presence of antibodies to concizumab. Additionally, pharmacokinetic parameters such as pre-dose (trough) concizumab plasma concentration, pre-dose thrombin peak, pre-dose free TFPI concentration, maximum concizumab plasma concentration (Cmax), and area under the concizumab plasma concentration-time curve (AUC) will be evaluated. These parameters will be measured at specific time points, including prior to concizumab administration at week 24 and from 0 to 24 hours post-dose at week 24.