Research Study to Look at How Well the Drug Concizumab Works in Your Body if You Have Haemophilia Without Inhibitors

Study Overview
=================
Brief Summary
-----------------
This study will test how well a new medicine called concizumab works in the body of people with haemophilia A or B without 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 have to inject themselves with the study medicine 1 time every day under the skin. This 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 up to 6.5 years. The length of time the participant will be in the study depends on when they agreed to take part or when the medicine is available for purchase in their country (21 April 2026 at the latest). Participants will have to come to the clinic for up to 40 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. If the participant attends extra visits due to the prescription medicine not being available for purchase in their country, these will be 14 weeks apart. Participants will be asked to record information in an electronic diary during the study and may also be asked to wear an activity tracker.

Official Title
-----------------
Efficacy and Safety of Concizumab Prophylaxis in Patients With Haemophilia A or B Without Inhibitors

Conditions
-----------------
Haemophilia A Without Inhibitors, Haemophilia B Without Inhibitors

Intervention / Treatment
-----------------
* Drug: Concizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
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 severe haemophilia A (FVIII below 1%) or B (FIX equal to or below 2%). 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. Presence of confirmed inhibitors 0.6 BU or greater at screening. 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.)

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomised to concizumab PPX/no PPX/ assigned into non-randomised arms, based on treatment before trial. Upon restart, patients randomised to arms 1/2 before pause will enter arm 4. Patients allocated to arms 3 & 4 before pause will re-enter initially allocated arm. Randomisation into arms 1/2 will be restarted with new patients. Main part is completed when patient completed 24 wks (excluding screening) in arm 1 or 32 wks (excluding screening) in arms 2-4. After main part, patients will have offer to continue in extension (ext.) part and receive treatment with product until concizumab is commercially available in their countries or until 21-Apr-26 at latest. Patients will be in ext. part for up to 257 (arms 2-4) or 265 wks (arm 1) for up to additional 128 (arms 2-4) or 136 wks (arm 1). Patient will receive last dose at home on day prior to visit 26a. Follow-up part will start on visit 26a and lasts for 7 wks and include reporting of bleeding episodes until visit 27a.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: No prophylaxis (PPX)<br>Haemophilia A (HA) and haemophilia B (HB) patients, previously treated on-demand, will be randomised 1:2 to no prophylaxis versus concizumab prophylaxis. In the extension phase, this group will receive treatment with concizumab. | Drug: Concizumab<br>* When patients are randomised/allocated to concizumab prophylaxis, they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week (Wk) 0) (arm 2, 3 and 4) or visit 9a (Wk 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 (Wk 6) or 9a.3 (Wk 30) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6) or 9a.2 (Wk 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 replacement therapy until visit 9a (week 24; end of main part). In the extension part, patients in arm 1 will receive daily concizumab subcutaneous injections.<br>|
| Experimental: Arm 2: Concizumab prophylaxis<br>HA and HB patients, previously treated on-demand, will be randomised 1:2 to no prophylaxis versus concizumab prophylaxis. | Drug: Concizumab<br>* When patients are randomised/allocated to concizumab prophylaxis, they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week (Wk) 0) (arm 2, 3 and 4) or visit 9a (Wk 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 (Wk 6) or 9a.3 (Wk 30) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6) or 9a.2 (Wk 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 replacement therapy until visit 9a (week 24; end of main part). In the extension part, patients in arm 1 will receive daily concizumab subcutaneous injections.<br>|
| Experimental: Arm 3: Concizumab prophylaxis<br>The HA patients enrolled into the concizumab phase 2 trial NN7415-4255 (explorer 5) will be offered enrolment into this arm. | Drug: Concizumab<br>* When patients are randomised/allocated to concizumab prophylaxis, they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week (Wk) 0) (arm 2, 3 and 4) or visit 9a (Wk 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 (Wk 6) or 9a.3 (Wk 30) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6) or 9a.2 (Wk 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 replacement therapy until visit 9a (week 24; end of main part). In the extension part, patients in arm 1 will receive daily concizumab subcutaneous injections.<br>|
| Experimental: Arm 4: Concizumab prophylaxis<br>Arm 4 will include patients previously on prophylaxis with factor products with a minimum of 24 weeks observation in NN7415-4322 (explorer 6) (at least 30 HA and 30 HB patients). In addition, arm 4 will also include: 1) Patients who were randomised to arms 1 and 2 before the treatment pause. 2) HA patients who were in NN7415-4255 (explorer 5) at the time of the treatment pause, and who have now completed explorer 5. 3) On demand patients included after arms 1 and 2 are closed. | Drug: Concizumab<br>* When patients are randomised/allocated to concizumab prophylaxis, they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week (Wk) 0) (arm 2, 3 and 4) or visit 9a (Wk 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 (Wk 6) or 9a.3 (Wk 30) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6) or 9a.2 (Wk 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 replacement therapy until visit 9a (week 24; end of main part). In the extension part, patients in arm 1 will receive daily concizumab subcutaneous injections.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For haemophilia A patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) | 
| For haemophilia B patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For haemophilia A patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes | This will be presented as 'count of episodes'. Arm 4 patients who have been on stable PPX at least 24 weeks in study 4322. For previous PPX (study 4322): From the point in time where PPX is stable and up until the end of study. Stable is defined as the time after an initial period on PPX treatment of at least 24 weeks. For concizumab PPX (trial 4307): From the point in time where the concizumab maintenance dose is confirmed, increased or decreased and up until the confirmatory analyses cut-off (at least 24 weeks). | Time frame is presented under 'outcome measure description' | 
| For haemophilia B patients without inhibitors: The number of treated spontaneous and traumatic bleeding episodes | This will be presented as 'count of episodes'. Arm 4 patients who have been on stable PPX at least 24 weeks in study 4322. For previous PPX (study 4322): From the point in time where PPX is stable and up until the end of study. Stable is defined as the time after an initial period on PPX treatment of at least 24 weeks. For concizumab PPX (trial 4307): From the point in time where the concizumab maintenance dose is confirmed, increased or decreased and up until the confirmatory analyses cut-off (at least 24 weeks). | Time frame is presented under 'outcome measure description' | 
| For haemophilia A patients without inhibitors: Number of treated spontaneous bleeding episodes | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) | 
| For haemophilia B patients without inhibitors: Number of treated spontaneous bleeding episodes | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) | 
| For haemophilia A patients without inhibitors: Number of treated spontaneous and traumatic joint bleeds | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) | 
| For haemophilia B patients without inhibitors: Number of treated spontaneous and traumatic joint bleeds | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) | 
| For haemophilia A patients without inhibitors: Number of treated spontaneous and traumatic target joint bleeds | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) | 
| For haemophilia B patients without inhibitors: Number of treated spontaneous and traumatic target joint bleeds | This will be presented as 'count of episodes'. | On demand (arm 1): From randomisation after the pause (Wk 0) up until start of concizumab treatment (Wk 24). Concizumab (arm 2): From start of the new concizumab dosing regimen (Wk 0) up until the confirmatory analyses cut-off (at least 32 weeks) | 
| Number of thromboembolic events | This will be presented as 'count of 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 confirmatory analyses cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the confirmatory analysis cut-off. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day). Week 0 after the pause is defined as the time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. | Time frame is presented under 'outcome measure description'. | 
| Number of thromboembolic events | This will be presented as 'count of events'. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous 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 296 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 confirmatory analyses cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the confirmatory analysis cut-off. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day). Week 0 after the pause is defined as the time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. | Time frame 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 the initial randomisation to on-demand administration or time of start of the previous 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 296 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 confirmatory analyses cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the confirmatory analysis cut-off. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day). Week 0 after the pause is defined as the time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. | Time frame 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 the initial randomisation to on-demand administration or time of start of the previous 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 296 weeks). | 
| Number of patients with antibodies to concizumab | This will be presented as 'count of participants'. 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 confirmatory analyses cut-off (at least 32 weeks). Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the confirmatory analysis cut-off. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous concizumab dosing regimen (0.25 mg/kg/day). Week 0 after the pause is defined as the time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. | Time frame is presented under 'outcome measure description'. | 
| Number of patients with antibodies to concizumab | This will be presented as 'count of participants'. Week 0 before the pause is defined as the time of the initial randomisation to on-demand administration or time of start of the previous 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 296 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) |