Research Study to Look at How Well the Drug Concizumab Works in Your Body if You Have Haemophilia With Inhibitors

Study Overview
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Brief Summary
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This study will test how well a new medicine called concizumab works in the body of people with haemophilia A or B with inhibitors. The purpose is to show that concizumab can prevent bleeds in the body and is safe to use. Participants who usually only take medicine to treat bleeds (on-demand) will be placed in one of two groups. In one group, participants will get study medicine from the start of the study. In the other group, participants will continue with their normal medicine and get study medicine after 6 months. Which treatment the participant gets is decided by chance. Participants who usually take medicine to prevent bleeds (prophylaxis treatment) or who are already being treated with concizumab (study medicine) will receive the study medicine from the start of the study. Participants will get 1 injection with the study medicine every day under the skin. This participants will have to do themselves and can be done at home. The study doctor will hand out the medicine in the form of a pen-injector. The pen-injector will contain the study medicine. The study will last for about six years. The length of time the participants will be in the study depends on when they agreed to take part or when the medicine is available for purchase in their country (12 November 2025 at the latest). Participants will have to come to the clinic for up to 41 times. The time between visits will be approximately 4 weeks for the first 6 to 12 months, depending on the group participants are in and approximately 8 weeks for the rest of the study. Participants will be asked to record information into an electronic diary during the study and may also be asked to wear an activity tracker.

Official Title
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Efficacy and Safety of Concizumab Prophylaxis in Patients With Haemophilia A or B With Inhibitors

Conditions
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Haemophilia A With Inhibitors, Haemophilia B With Inhibitors

Intervention / Treatment
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* Drug: Concizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial. Male aged 12 years or older at the time of signing informed consent. Congenital Haemophilia A or B of any severity with documented history of inhibitor (equal to or above 0.6 Bethesda Units (BU). Patient has been prescribed, or in need of, treatment with bypassing agents in the last 24 weeks prior to screening (for patients not previously enrolled in NN7415-4310 (explorer 4)). Exclusion Criteria: Known or suspected hypersensitivity to any constituent of the trial product or related products. Known inherited or acquired coagulation disorder other than congenital haemophilia. Ongoing or planned Immune Tolerance Induction treatment. History of thromboembolic disease (includes arterial and venous thrombosis including myocardial infarction, pulmonary embolism, cerebral infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events and peripheral artery occlusion). Current clinical signs of, or treatment for thromboembolic disease. Patients who in the judgement of the investigator are considered at high risk of thromboembolic events (thromboembolic risk factors could include, but are not limited to, hypercholesterolemia, diabetes mellitus, hypertension, obesity, smoking, family history of thromboembolic events, arteriosclerosis, other conditions associated with increased risk of thromboembolic events.)
Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomised to concizumab prophylaxis (ppx) or no ppx or assigned into non-randomised treatment arms, based on their treatment regimen before entering the trial. Main part of trial is completed when participant has completed at least 24 weeks of participation in arm 1 or 32 weeks in arms 2, 3 and 4. After main part, all participants will be offered to continue in extension part and receive treatment until concizumab is commercially available in their countries or until 12 Nov 2025 for up to 241 weeks (arms 1-4) or up to 265 weeks (randomised to arm 1 before the pause). After extension part, participant will enter safety follow-up part on visit 26a, which defines end-of-treatment. Participant will receive last dose of trial drug at home on day prior to visit 26a. On visit 26a, participants will either start up commercially available concizumab or revert to previous ppx schedule or on-demand regimen. Follow-up part will start on visit 26a and lasts for 7 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: No prophylaxis<br>Haemophilia A with inhibitors (HAwI) and haemophilia B with inhibitors (HBwI) patients, previously treated on-demand, will be randomised 1:2 to no prophylaxis versus concizumab prophylaxis. In the extension part, patients in arm 1 will receive daily concizumab subcutaneous (s.c., under the skin) injections. | Drug: Concizumab<br>* Concizumab will be administered daily subcutaneously (s.c., under the skin). When patients are randomised to concizumab prophylaxis they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week 0: arm 2, 3 & 4) or visit 9a (week 24: arm 1) followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week dose adjustment period on 0.20 mg/kg concizumab, the patients can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 4a.1 (week 6: arm 2, 3 & 4) or 9a.3 (week 30: arm 1) and will be based on the concizumab exposure level measured at the previous visit 4a (week 4) or 9a.2 (week 28). Patients who have concizumab exposure levels of 200-4000 ng/mL will stay at 0.20 mg/kg concizumab. Patients in arm 1 will continue on-demand treatment with their usual bypassing product until visit 9a (week 24: end of main part for arm 1).<br>|
| Experimental: Arm 2: Concizumab prophylaxis<br>HAwI and HBwI patients, previously treated on-demand, will be randomised 1:2 to no prophylaxis versus concizumab prophylaxis. | Drug: Concizumab<br>* Concizumab will be administered daily subcutaneously (s.c., under the skin). When patients are randomised to concizumab prophylaxis they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week 0: arm 2, 3 & 4) or visit 9a (week 24: arm 1) followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week dose adjustment period on 0.20 mg/kg concizumab, the patients can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 4a.1 (week 6: arm 2, 3 & 4) or 9a.3 (week 30: arm 1) and will be based on the concizumab exposure level measured at the previous visit 4a (week 4) or 9a.2 (week 28). Patients who have concizumab exposure levels of 200-4000 ng/mL will stay at 0.20 mg/kg concizumab. Patients in arm 1 will continue on-demand treatment with their usual bypassing product until visit 9a (week 24: end of main part for arm 1).<br>|
| Experimental: Arm 3: Concizumab prophylaxis<br>The HAwI and HBwI patients enrolled into the concizumab phase 2 trial (NN7415-4310) at time of transfer will be offered enrolment into this trial. It is required that these patients are on concizumab prophylaxis up until enrolment into the trial. These patients will continue concizumab prophylaxis. | Drug: Concizumab<br>* Concizumab will be administered daily subcutaneously (s.c., under the skin). When patients are randomised to concizumab prophylaxis they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week 0: arm 2, 3 & 4) or visit 9a (week 24: arm 1) followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week dose adjustment period on 0.20 mg/kg concizumab, the patients can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 4a.1 (week 6: arm 2, 3 & 4) or 9a.3 (week 30: arm 1) and will be based on the concizumab exposure level measured at the previous visit 4a (week 4) or 9a.2 (week 28). Patients who have concizumab exposure levels of 200-4000 ng/mL will stay at 0.20 mg/kg concizumab. Patients in arm 1 will continue on-demand treatment with their usual bypassing product until visit 9a (week 24: end of main part for arm 1).<br>|
| Experimental: Arm 4: Concizumab prophylaxis<br>Patients previously on prophylaxis with by-passing agents and on-demand patients who are screened at a timepoint where the required number of patients in arms 1 and 2 have been randomised. These patients will, if eligible, be enrolled into the trial and will initiate concizumab prophylaxis at visit 2a (week 0). | Drug: Concizumab<br>* Concizumab will be administered daily subcutaneously (s.c., under the skin). When patients are randomised to concizumab prophylaxis they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week 0: arm 2, 3 & 4) or visit 9a (week 24: arm 1) followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week dose adjustment period on 0.20 mg/kg concizumab, the patients can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 4a.1 (week 6: arm 2, 3 & 4) or 9a.3 (week 30: arm 1) and will be based on the concizumab exposure level measured at the previous visit 4a (week 4) or 9a.2 (week 28). Patients who have concizumab exposure levels of 200-4000 ng/mL will stay at 0.20 mg/kg concizumab. Patients in arm 1 will continue on-demand treatment with their usual bypassing product until visit 9a (week 24: end of main part for arm 1).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of treated spontaneous and traumatic bleeding episodes | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation (week 0) up until start of concizumab treatment (at least 24 weeks). Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the primary analysis cut-off (at least 32 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 36 Item short form health survey version 2 (SF36v2) bodily pain | This will be presented as 'score on a scale'. The bodily pain subscale of the SF-36v2 questionnaire consists of 2 items. Subscale scores range from 0-100 and are transformed into population norm adjusted T-scores. A higher score indicates a better outcome on this subscale. | From start of treatment (week 0) until week 24. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. | 
| Change in SF36v2 physical functioning | This will be presented as 'score on a scale'. The physical function subscale of the SF-36v2 questionnaire consists of 1 item with 10 subitems. Subscale scores range from 0-100 and are transformed into population norm adjusted T-scores. A higher score indicates a better outcome on this subscale. | From start of treatment (week 0) until week 24. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. | 
| Number of treated spontaneous bleeding episodes | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation (week 0) up until start of concizumab treatment (at least 24 weeks) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Number of treated spontaneous and traumatic joint bleeds | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation (week 0) up until start of concizumab treatment (at least 24 weeks) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Number of treated spontaneous and traumatic target joint bleeds | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation (week 0) up until start of concizumab treatment (at least 24 weeks) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Number of thromboembolic events | This will be presented as 'count of thromboembolic events'. On demand (arm 1 main part): From randomisation to on demand treatment up until start of concizumab treatment. Concizumab (arms 2-4): Before the pause: From start of concizumab treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment (week 0) up until the primary analysis cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of the new concizumab dosing regimen (week 25) up until the primary analysis cut-off. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). Week 0, after the pause is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. | Timeframe is presented under 'outcome measure description' | 
| Number of thromboembolic events | This will be presented as 'count of thromboembolic events'. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). | Concizumab: Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment up until the end of trial (up to 280 weeks). | 
| Number of hypersensitivity type reactions | This will be presented as 'count of hypersensitivity type reactions'. On demand (arm 1 main part): From randomisation to on demand treatment up until start of concizumab treatment. Concizumab (arms 2-4): Before the pause: From start of concizumab treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment (week 0) up until the primary analysis cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of the new concizumab dosing regimen (week 25) up until the primary analysis cut-off. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). Week 0, after the pause is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. | Timeframe is presented under 'outcome measure description' | 
| Number of hypersensitivity type reactions | This will be presented as 'count of hypersensitivity type reactions'. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). | Concizumab: Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment up until the end of trial (up to 280 weeks). | 
| Number of injection site reactions | This will be presented as 'count of injection site reactions'. On demand (arm 1 main part): From randomisation to on demand treatment up until start of concizumab treatment. Concizumab (arms 2-4): Before the pause: From start of concizumab treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment (week 0) up until the primary analysis cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of the new concizumab dosing regimen (week 25) up until the primary analysis cut-off. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). Week 0, after the pause is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. | Timeframe is presented under 'outcome measure description' | 
| Number of injection site reactions | This will be presented as 'count of injection site reactions'. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). | Concizumab: Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment up until the end of trial (up to 280 weeks). | 
| Number of patients with antibodies to concizumab | This will be presented as 'count of patients'. Concizumab (arms 2-4): Before the pause: From start of concizumab treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment (week 0) up until the primary analysis cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of the new concizumab dosing regimen (week 25) up until the primary analysis cut-off. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). Week 0, after the pause is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. | Timeframe is presented under 'outcome measure description' | 
| Number of patients with antibodies to concizumab | This will be presented as 'count of patients'. Week 0, before the pause is defined as the time of randomisation to on-demand administration or time of start of the initial concizumab dosing regimen (0.25 mg/kg/day). | Concizumab: Before the pause: From start of treatment (week 0) up until 7 weeks after the treatment was paused. After the pause: From start of concizumab treatment up until the end of trial (up to 280 weeks). | 
| Pre-dose (trough) concizumab plasma concentration (Ctrough) | This will be measured in 'ng/mL'. | Prior to the concizumab administration at week 24 (after restart) | 
| Pre-dose thrombin peak | This will be measured in 'nmol/L'. | Prior to the concizumab administration at week 24 (after restart) | 
| Pre-dose free tissue factor pathway inhibitor (TFPI) concentration | This will be measured in 'ng/mL'. | Prior to the concizumab administration at week 24 (after restart) | 
| Maximum concizumab plasma concentration (Cmax) | This will be measured in 'ng/mL'. | From 0 to 24 hours where 0 is time of the concizumab dose at week 24 (after restart) | 
| Area under the concizumab plasma concentration-time curve (AUC) | This will be measured in 'ng*hr/mL'. | From 0 to 24 hours where 0 is time of the concizumab dose at week 24 (after restart) |