Haemophilia A Without Inhibitors, Haemophilia B Without Inhibitors
Conditions
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 8 years. The length of time the participant will be in the study depends on when they agreed to take part and when the medicine is available for purchase in their country (or 31 December 2027 at the latest). 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.
Interventions
DRUGConcizumab
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.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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 31-Dec-2027 at latest. Patients will be in the extension part for up to 345 weeks (arms 2-4) or up to 353 weeks (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.
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
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.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | On demand (arm 1): From week 0 up until start of concizumab treatment (week 24); Concizumab (arm 2): From week 0 up until the confirmatory analyses cut-off | Rate of treated spontaneous and traumatic bleeding episodes for haemophilia A participants without inhibitors is presented. The observation period used for reporting this endpoint is on-treatment without ancillary therapy excluding data before restart (OTwoATexBR). It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of annualised bleeding rate (ABR). Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. Confirmatory analyses cut-off was defined as when all participants on no PPX (arm 1) had completed the 24-week visit or withdrawn and all participants on concizumab PPX (in arms 2 and 4) had completed the 32-week visit or withdrawn. |
| Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | On demand (arm 1): From week 0 up until start of concizumab treatment (week 24); Concizumab (arm 2): From week 0 up until the confirmatory analyses cut-off | Rate of treated spontaneous and traumatic bleeding episodes for haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. Confirmatory analyses cut-off was defined as when all participants on no PPX (arm 1) had completed the 24-week visit or withdrawn and all participants on concizumab PPX (in arms 2 and 4) had completed the 32-week visit or withdrawn. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | For previous PPX (study 4322): After an initial period on PPX treatment of at least 24 weeks until end of study (maximum 115 weeks) For concizumab PPX (trial 4307): After an initial 5-8 weeks dose adjustment period and up until 56 week cut off | Rate of treated spontaneous and traumatic bleeding episodes for haemophilia A participants without inhibitors in arm 4 participants who had been on stable PPX at least 24 weeks in study 4322 is presented. The observation period used for reporting this endpoint is on stable treatment without ancillary therapy excluding data before restart (OT stable woATexBR). It is defined as the time period where participants are on stable PPX in study NN7415-4322 combined with the time period after the treatment pause in NN7415-4307 where the same participants are on the maintenance dose and have not used factor-containing products not related to treatment of a bleed. The data is reported in the terms of ABR. |
| Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | For previous PPX (study 4322): After an initial period on PPX treatment of at least 24 weeks until end of study (maximum 115 weeks) For concizumab PPX (trial 4307): After an initial 5-8 weeks dose adjustment period and up until 56 week cut off | Rate of treated spontaneous and traumatic bleeding episodes for haemophilia B participants without inhibitors in arm 4 participants who had been on stable PPX at least 24 weeks in study 4322 is presented. The observation period used for reporting this endpoint is OT stable woATexBR. It is defined as the time period where participants are on stable PPX in study NN7415-4322 combined with the time period after the treatment pause in NN7415-4307 where the same participants are on the maintenance dose and have not used factor-containing products not related to treatment of a bleed. The data is reported in the terms of ABR. |
| Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous Bleeding Episodes | On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off | Rate of treated spontaneous bleeding episodes for haemophilia A participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. |
| Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous Bleeding Episodes | On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off | Rate of treated spontaneous bleeding episodes for haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. |
| Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Joint Bleeding Episodes | On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off | Rate of treated spontaneous and traumatic joint bleeding episodes for haemophilia A participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. |
| Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Joint Bleeding Episodes | On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off | Rate of treated spontaneous and traumatic joint bleeding episodes for haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. |
| Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Target Joint Bleeding Episodes | On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off | Rate of treated spontaneous and traumatic target joint bleeding episodes for haemophilia A participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. |
| Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Target Joint Bleeding Episodes | On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off | Rate of treated spontaneous and traumatic target joint bleeding episodes for haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. |
| Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | On demand (arm 1): from week 0 until start of concizumab treatment (week 24). Concizumab (arms 2-4): From week 0 up until the 56 week cut-off. Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the 56 week cut-off | Number of thromboembolic events in haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is on-treatment (OT). It is defined as the time period where participants were considered to be affected by no PPX (on-demand treatment) or concizumab PPX. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. |
| Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | On demand (arm 1): from week 0 until start of concizumab treatment (week 24). Concizumab (arms 2-4): From week 0 up until the 56 week cut-off. Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the 56 week cut-off | Number of hypersensitivity type reactions in haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OT. It is defined as the time period where participants were considered to be affected by no PPX (on-demand treatment) or concizumab PPX. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. |
| Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | On demand (arm 1 main part): from randomisation (week 0) until start of concizumab treatment (week 24). Concizumab (arms 2-4): From week 0 up until the 56 week cut-off. Concizumab (arm 1 extension part): From week 25 up until the 56 week cut-off | Number of injection site reactions in haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OT. It is defined as the time period where participants were considered to be affected by no PPX (on-demand treatment) or concizumab PPX. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. |
| Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Participants With Antibodies to Concizumab | Concizumab (arms 2-4): From start of concizumab treatment (week 0) up until the 56 week cut-off. Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the 56 week cut-off | — |
| Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | Pre-dose (prior to the concizumab administration at week 24) | Ctrough for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is on-treatment without data before re-start (OTexBR). It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen. |
| Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Thrombin Peak | Pre-dose (prior to the concizumab administration at week 24) | Pre-dose thrombin peak for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTexBR. It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen. |
| Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | Pre-dose (prior to the concizumab administration at week 24) | Pre-dose free TFPI for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTexBR. It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen. |
| Haemophila A and Haemophilia B Participants Without Inhibitors: Maximum Concizumab Plasma Concentration (Cmax) | Pre-dose, Week 24: 3 hours (h), 6h, 9h, 24h | Cmax for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTexBR. It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen. |
| Haemophila A and Haemophilia B Participants Without Inhibitors: Area Under the Concizumab Plasma Concentration-time Curve (AUC) | Pre-dose, Week 24: 3 hours (h), 6h, 9h, 24h | AUC for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTexBR. It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen. |
Countries
Algeria, Australia, Bosnia and Herzegovina, Bulgaria, Canada, Croatia, Denmark, Estonia, France, Germany, Hungary, India, Israel, Italy, Japan, Lithuania, Malaysia, Mexico, Poland, Portugal, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Reporting Anchor and Disclosure (1452)
Novo Nordisk A/S
Participant flow
Recruitment details
The trial was conducted at 68 sites in 31 countries.
Pre-assignment details
Data is reported till cutoff date 27-Dec-2022 and study is still ongoing. Initially, participants were randomised to arm 1 or 2 or to non-randomised arms 3 or 4. There was a treatment pause due to investigation of thromboembolic events. After treatment pause, participants randomised to arms 1 or 2 before pause entered arm 4. Participants allocated to arms 3 and 4 before pause re-entered arms initially allocated to. New participants were randomized in arms 1and 2.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA Participants with HA received their on-demand treatment for a minimum of 24 weeks. After treatment pause, participants initially randomised to arm 1 were to enter arm 4. Subsequently, following the main phase, participants transitioned to the new dosing regimen for concizumab and were scheduled to undergo concizumab prophylaxis in the trial's extension phase. | 9 |
| Arm 1: Previous OnD Treatment: No PPX - Participants With HB Participants with HB received their on-demand treatment for a minimum of 24 weeks. After treatment pause, participants initially randomised to arm 1 were to enter arm 4. Subsequently, following the main phase, participants transitioned to the new dosing regimen for concizumab and were scheduled to undergo concizumab prophylaxis in the trial's extension phase. | 12 |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA Participants with HA received a loading dose of 1.0 milligrams per kilograms (mg/kg) concizumab subcutaneously followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week maintenance dose setting period on 0.20 mg/kg concizumab, the participants could be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab or stayed at 0.20mg/kg. After treatment pause, participants initially randomised to arm 2 were to enter arm 4. | 18 |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HB Participants with HB received a loading dose of 1.0 mg/kg concizumab subcutaneously followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week maintenance dose setting period on 0.20 mg/kg concizumab, the participants could be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab or stayed at 0.20mg/kg. After treatment pause, participants initially randomised to arm 2 were to enter arm 4. | 24 |
| Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA Participants with HA received a loading dose (participants entering from the phase 2 trial \[N7415-4255\] (NCT03196297) were not to receive a loading dose) of 1.0 mg/kg concizumab subcutaneously followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week maintenance dose setting period on 0.20 mg/kg concizumab, the participants could be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab or stayed at 0.20mg/kg. | 9 |
| Arm 4: Concizumab PPX - Participants With HA Participants with HA previously on PPX with factor products and a minimum of 24 weeks of observation in the non interventional study 4322 (NCT03741881) were allocated to Arm 4. Additionally, Arm 4 also included participants who were randomised to arms 1 (no PPX) and 2 (concizumab PPX) before the treatment pause, participants who were in the phase 2 trial 4255 at the time of the treatment pause, and who had subsequently completed the trial when concizumab treatment was restarted and on-demand participants included after arms 1 and 2 were closed. The original dosing regimen was a loading s.c. dose of 1.0 mg/kg concizumab on the first day of treatment, followed by a maintenance dose of 0.25 mg/kg concizumab given as a daily s.c. injection from the second day and onwards. After the concizumab treatment pause and the treatment restart, participants received a loading dose of 1.0 mg/kg concizumab at visit 2a followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week maintenance dose setting period on 0.20 mg/kg concizumab, the participants could have their dose increased to 0.25 mg/kg or decreased to 0.15 mg/kg concizumab or they could remain at a dose of 0.20 mg/kg. | 46 |
| Arm 4: Concizumab PPX - Participants With HB Participants with HB previously on PPX with factor products and a minimum of 24 weeks of observation in the non interventional study 4322 (NCT03741881) were allocated to Arm 4. Additionally, Arm 4 also included participants who were randomised to arms 1 (no PPX) and 2 (concizumab PPX) before the treatment pause, participants who were in the phase 2 trial 4255 at the time of the treatment pause, and who had subsequently completed the trial when concizumab treatment was restarted and on-demand participants included after arms 1 and 2 were closed. The original dosing regimen was a loading s.c. dose of 1.0 mg/kg concizumab on the first day of treatment, followed by a maintenance dose of 0.25 mg/kg concizumab given as a daily s.c. injection from the second day and onwards. After the concizumab treatment pause and the treatment restart, participants received a loading dose of 1.0 mg/kg concizumab at visit 2a followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week maintenance dose setting period on 0.20 mg/kg concizumab, the participants could have their dose increased to 0.25 mg/kg or decreased to 0.15 mg/kg concizumab or they could remain at a dose of 0.20 mg/kg. | 30 |
| Total | 148 |
Baseline characteristics
| Characteristic | Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Arm 1: Previous OnD Treatment: No PPX - Participants With HB | Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HB | Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA | Arm 4: Concizumab PPX - Participants With HA | Arm 4: Concizumab PPX - Participants With HB | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 34.7 Years STANDARD_DEVIATION 21.3 | 30.4 Years STANDARD_DEVIATION 17.5 | 30.7 Years STANDARD_DEVIATION 9.6 | 28.0 Years STANDARD_DEVIATION 12 | 43.7 Years STANDARD_DEVIATION 18 | 30.4 Years STANDARD_DEVIATION 13.4 | 31.6 Years STANDARD_DEVIATION 13.3 | 31.4 Years STANDARD_DEVIATION 14.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants | 3 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 11 Participants | 18 Participants | 23 Participants | 7 Participants | 41 Participants | 27 Participants | 135 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 6 Participants | 8 Participants | 10 Participants | 3 Participants | 13 Participants | 1 Participants | 42 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 7 Participants | 6 Participants | 9 Participants | 12 Participants | 6 Participants | 30 Participants | 27 Participants | 97 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 12 Participants | 18 Participants | 24 Participants | 9 Participants | 46 Participants | 30 Participants | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 7 | 0 / 18 | 0 / 10 | 1 / 52 | 0 / 12 | 0 / 10 | 0 / 24 | 0 / 30 |
| other Total, other adverse events | 2 / 9 | 5 / 7 | 10 / 18 | 8 / 10 | 40 / 52 | 2 / 12 | 5 / 10 | 12 / 24 | 24 / 30 |
| serious Total, serious adverse events | 0 / 9 | 0 / 7 | 1 / 18 | 1 / 10 | 10 / 52 | 2 / 12 | 0 / 10 | 6 / 24 | 2 / 30 |
Outcome results
Primary
Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes
Rate of treated spontaneous and traumatic bleeding episodes for haemophilia A participants without inhibitors is presented. The observation period used for reporting this endpoint is on-treatment without ancillary therapy excluding data before restart (OTwoATexBR). It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of annualised bleeding rate (ABR). Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. Confirmatory analyses cut-off was defined as when all participants on no PPX (arm 1) had completed the 24-week visit or withdrawn and all participants on concizumab PPX (in arms 2 and 4) had completed the 32-week visit or withdrawn.
Time frame: On demand (arm 1): From week 0 up until start of concizumab treatment (week 24); Concizumab (arm 2): From week 0 up until the confirmatory analyses cut-off
Population: FAS included all participants randomised to the new concizumab PPX dosing regimen or on-demand treatment after the treatment pause or allocated to arm 3 or 4 with the new concizumab PPX dosing regimen. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 19.6 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 2.9 Events per year |
p-value: <0.00195% CI: [0.07, 0.29]Negative binomial regression
Primary
Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes
Rate of treated spontaneous and traumatic bleeding episodes for haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen. Confirmatory analyses cut-off was defined as when all participants on no PPX (arm 1) had completed the 24-week visit or withdrawn and all participants on concizumab PPX (in arms 2 and 4) had completed the 32-week visit or withdrawn.
Time frame: On demand (arm 1): From week 0 up until start of concizumab treatment (week 24); Concizumab (arm 2): From week 0 up until the confirmatory analyses cut-off
Population: FAS included all participants randomised to the new concizumab PPX dosing regimen or on-demand treatment after the treatment pause or allocated to arm 3 or 4 with the new concizumab PPX dosing regimen. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 14.9 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 1.6 Events per year |
p-value: <0.00195% CI: [0.1, 0.45]Negative binomial regression
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Area Under the Concizumab Plasma Concentration-time Curve (AUC)
AUC for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTexBR. It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen.
Time frame: Pre-dose, Week 24: 3 hours (h), 6h, 9h, 24h
Population: SAS was defined as all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analysed = Participants with available data for the outcome measure. The endpoint is applicable for reported arms \[for participants with HA (arm 2, arm 3, arm 4) and participants with HB (arm 2, arm 4)\] only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Area Under the Concizumab Plasma Concentration-time Curve (AUC) | 23582.5 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 68.2 |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Area Under the Concizumab Plasma Concentration-time Curve (AUC) | 11082.7 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 268 |
| Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Area Under the Concizumab Plasma Concentration-time Curve (AUC) | 20355.6 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 135.2 |
| Arm 4: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Area Under the Concizumab Plasma Concentration-time Curve (AUC) | 13020.5 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 182.7 |
| Extension Phase Arm 1: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Area Under the Concizumab Plasma Concentration-time Curve (AUC) | 16191.8 nanograms*hour/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 118.2 |
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Maximum Concizumab Plasma Concentration (Cmax)
Cmax for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTexBR. It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen.
Time frame: Pre-dose, Week 24: 3 hours (h), 6h, 9h, 24h
Population: SAS was defined as all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analysed = Participants with available data for the outcome measure. The endpoint is applicable for reported arms \[for participants with HA (arm 2, arm 3, arm 4) and participants with HB (arm 2, arm 4)\] only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Maximum Concizumab Plasma Concentration (Cmax) | 1158.2 ng/mL | Geometric Coefficient of Variation 61.9 |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Maximum Concizumab Plasma Concentration (Cmax) | 583.4 ng/mL | Geometric Coefficient of Variation 282.2 |
| Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Maximum Concizumab Plasma Concentration (Cmax) | 1029.7 ng/mL | Geometric Coefficient of Variation 130.9 |
| Arm 4: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Maximum Concizumab Plasma Concentration (Cmax) | 689.2 ng/mL | Geometric Coefficient of Variation 190.5 |
| Extension Phase Arm 1: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Maximum Concizumab Plasma Concentration (Cmax) | 828.0 ng/mL | Geometric Coefficient of Variation 111.2 |
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions
Number of hypersensitivity type reactions in haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OT. It is defined as the time period where participants were considered to be affected by no PPX (on-demand treatment) or concizumab PPX. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): from week 0 until start of concizumab treatment (week 24). Concizumab (arms 2-4): From week 0 up until the 56 week cut-off. Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the 56 week cut-off
Population: SAS was defined as all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analysed = Participants with available data for the outcome measure. The endpoint is applicable for reported arms \[for participants with HA (arm1, arm 2, arm 3, arm 4, arm 1 extension part) and participants with HB (arm 1, arm 2, arm 4, arm 1 extension part)\] only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | 0 Reactions |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | 0 Reactions |
| Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | 0 Reactions |
| Arm 4: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | 0 Reactions |
| Extension Phase Arm 1: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | 0 Reactions |
| Arm 1: Previous OnD Treatment: No PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | 0 Reactions |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | 0 Reactions |
| Arm 4: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | 0 Reactions |
| Extension Phase Arm 1: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions | 0 Reactions |
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Hypersensitivity Type Reactions
Time frame: From week 0 to end of trial (up until 384 weeks)
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions
Time frame: From week 0 to end of trial (up until 384 weeks)
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions
Number of injection site reactions in haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OT. It is defined as the time period where participants were considered to be affected by no PPX (on-demand treatment) or concizumab PPX. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1 main part): from randomisation (week 0) until start of concizumab treatment (week 24). Concizumab (arms 2-4): From week 0 up until the 56 week cut-off. Concizumab (arm 1 extension part): From week 25 up until the 56 week cut-off
Population: SAS was defined as all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analysed = Participants with available data for the outcome measure. The endpoint is applicable for reported arms \[for participants with HA (arm1, arm 2, arm 3, arm 4, arm 1 extension part) and participants with HB (arm 1, arm 2, arm 4, arm 1 extension part)\] only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | 0 Reactions |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | 1 Reactions |
| Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | 0 Reactions |
| Arm 4: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | 14 Reactions |
| Extension Phase Arm 1: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | 1 Reactions |
| Arm 1: Previous OnD Treatment: No PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | 0 Reactions |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | 2 Reactions |
| Arm 4: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | 28 Reactions |
| Extension Phase Arm 1: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Injection Site Reactions | 0 Reactions |
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Participants With Antibodies to Concizumab
Time frame: Concizumab (arms 2-4): From start of concizumab treatment (week 0) up until the 56 week cut-off. Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the 56 week cut-off
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Participants With Antibodies to Concizumab
Time frame: From week 0 to end of trial (up until 384 weeks)
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events
Time frame: From week 0 to end of trial (up to 384 weeks)
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events
Number of thromboembolic events in haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is on-treatment (OT). It is defined as the time period where participants were considered to be affected by no PPX (on-demand treatment) or concizumab PPX. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): from week 0 until start of concizumab treatment (week 24). Concizumab (arms 2-4): From week 0 up until the 56 week cut-off. Concizumab (arm 1 extension part): From start of concizumab treatment (week 25) up until the 56 week cut-off
Population: SAS was defined as all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analysed = Participants with available data for the outcome measure. The endpoint is applicable for reported arms \[for participants with HA (arm1, arm 2, arm 3, arm 4, arm 1 extension part) and participants with HB (arm 1, arm 2, arm 4, arm 1 extension part)\] only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | 0 Events |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | 0 Events |
| Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | 0 Events |
| Arm 4: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | 4 Events |
| Extension Phase Arm 1: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | 0 Events |
| Arm 1: Previous OnD Treatment: No PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | 0 Events |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | 0 Events |
| Arm 4: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | 0 Events |
| Extension Phase Arm 1: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Number of Thromboembolic Events | 0 Events |
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration
Pre-dose free TFPI for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTexBR. It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen.
Time frame: Pre-dose (prior to the concizumab administration at week 24)
Population: SAS was defined as all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analysed = Participants with available data for the outcome measure. The endpoint is applicable for reported arms \[for participants with HA (arm 1, arm 2, arm 3, arm 4) and participants with HB (arm 1, arm 2, arm 4)\] only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 70.1 ng/mL | Geometric Coefficient of Variation 12.3 |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 11.1 ng/mL | Geometric Coefficient of Variation 74.8 |
| Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 15.9 ng/mL | Geometric Coefficient of Variation 75.8 |
| Arm 4: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 9.6 ng/mL | Geometric Coefficient of Variation 87.9 |
| Extension Phase Arm 1: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 88.1 ng/mL | Geometric Coefficient of Variation 14.6 |
| Arm 1: Previous OnD Treatment: No PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 16.3 ng/mL | Geometric Coefficient of Variation 130.3 |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 10.5 ng/mL | Geometric Coefficient of Variation 107.4 |
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Thrombin Peak
Pre-dose thrombin peak for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTexBR. It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen.
Time frame: Pre-dose (prior to the concizumab administration at week 24)
Population: SAS was defined as all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analysed = Participants with available data for the outcome measure. The endpoint is applicable for reported arms \[for participants with HA (arm 1, arm 2, arm 3, arm 4) and participants with HB (arm 1, arm 2, arm 4)\] only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Thrombin Peak | 19.9 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 117.7 |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Thrombin Peak | 98.3 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 53.3 |
| Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Thrombin Peak | 92.3 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 69 |
| Arm 4: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Thrombin Peak | 92.1 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 57.8 |
| Extension Phase Arm 1: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Thrombin Peak | 9.6 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 110.7 |
| Arm 1: Previous OnD Treatment: No PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Thrombin Peak | 54.6 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 111.9 |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HB | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose Thrombin Peak | 79.4 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 57.1 |
Secondary
Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough)
Ctrough for haemophilia A and haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is on-treatment without data before re-start (OTexBR). It is defined as the time period after restart where participants were considered to be affected by no PPX (on-demand treatment) or treatment with the new concizumab regimen.
Time frame: Pre-dose (prior to the concizumab administration at week 24)
Population: SAS was defined as all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analysed = Participants with available data for the outcome measure. The endpoint is applicable for reported arms \[for participants with HA (arm 2, arm 3, arm 4) and participants with HB (arm 2, arm 4)\] only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | 767.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 112.4 |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | 612.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 274.9 |
| Arm 3: Concizumab Non-naive: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | 729.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 158.6 |
| Arm 4: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | 413.6 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 234.7 |
| Extension Phase Arm 1: Concizumab PPX - Participants With HA | Haemophila A and Haemophilia B Participants Without Inhibitors: Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | 719.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 189.7 |
Secondary
Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes
Rate of treated spontaneous and traumatic bleeding episodes for haemophilia A participants without inhibitors in arm 4 participants who had been on stable PPX at least 24 weeks in study 4322 is presented. The observation period used for reporting this endpoint is on stable treatment without ancillary therapy excluding data before restart (OT stable woATexBR). It is defined as the time period where participants are on stable PPX in study NN7415-4322 combined with the time period after the treatment pause in NN7415-4307 where the same participants are on the maintenance dose and have not used factor-containing products not related to treatment of a bleed. The data is reported in the terms of ABR.
Time frame: For previous PPX (study 4322): After an initial period on PPX treatment of at least 24 weeks until end of study (maximum 115 weeks) For concizumab PPX (trial 4307): After an initial 5-8 weeks dose adjustment period and up until 56 week cut off
Population: Intra-participant analysis set (IPAS) included participants in arm 4 that were on a stable PPX regimen for at least 24 weeks in NN7415-4322 and who entered the maintenance period in this trial NN7415-4307. The participants reported in both arms/groups represent the same 29 participants, with results reported from Study 4322 and this study (Study 4307). The endpoint is only defined for arm 4 (previous PPX-study 4322) and arm 4 (concizumab PPX-study 4307) as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 2.2 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 1.7 Events per year |
Secondary
Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Joint Bleeding Episodes
Rate of treated spontaneous and traumatic joint bleeding episodes for haemophilia A participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off
Population: FAS included all participants randomised to the new concizumab PPX dosing regimen or on-demand treatment after the treatment pause or allocated to arm 3 or 4 with the new concizumab PPX dosing regimen. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Joint Bleeding Episodes | 13.0 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Joint Bleeding Episodes | 2.0 Events per year |
Secondary
Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Target Joint Bleeding Episodes
Rate of treated spontaneous and traumatic target joint bleeding episodes for haemophilia A participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off
Population: FAS included all participants randomised to the new concizumab PPX dosing regimen or on-demand treatment after the treatment pause or allocated to arm 3 or 4 with the new concizumab PPX dosing regimen. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Target Joint Bleeding Episodes | 4.3 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Target Joint Bleeding Episodes | 1.7 Events per year |
Secondary
Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous Bleeding Episodes
Rate of treated spontaneous bleeding episodes for haemophilia A participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off
Population: FAS included all participants randomised to the new concizumab PPX dosing regimen or on-demand treatment after the treatment pause or allocated to arm 3 or 4 with the new concizumab PPX dosing regimen. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous Bleeding Episodes | 19.3 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia A Participants Without Inhibitors: Rate of Treated Spontaneous Bleeding Episodes | 1.0 Events per year |
Secondary
Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes
Rate of treated spontaneous and traumatic bleeding episodes for haemophilia B participants without inhibitors in arm 4 participants who had been on stable PPX at least 24 weeks in study 4322 is presented. The observation period used for reporting this endpoint is OT stable woATexBR. It is defined as the time period where participants are on stable PPX in study NN7415-4322 combined with the time period after the treatment pause in NN7415-4307 where the same participants are on the maintenance dose and have not used factor-containing products not related to treatment of a bleed. The data is reported in the terms of ABR.
Time frame: For previous PPX (study 4322): After an initial period on PPX treatment of at least 24 weeks until end of study (maximum 115 weeks) For concizumab PPX (trial 4307): After an initial 5-8 weeks dose adjustment period and up until 56 week cut off
Population: IPAS included participants in arm 4 that were on a stable PPX regimen for at least 24 weeks in NN7415-4322 and who entered the maintenance period in this trial NN7415-4307. The participants reported in both arms/groups represent the same 29 participants, with results reported from Study 4322 and this study (Study 4307). The endpoint is only defined for arm 4 (previous PPX-study 4322) and arm 4 (concizumab PPX-study 4307) as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 2.1 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 1.3 Events per year |
Secondary
Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Joint Bleeding Episodes
Rate of treated spontaneous and traumatic joint bleeding episodes for haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off
Population: FAS included all participants randomised to the new concizumab PPX dosing regimen or on-demand treatment after the treatment pause or allocated to arm 3 or 4 with the new concizumab PPX dosing regimen. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Joint Bleeding Episodes | 10.0 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Joint Bleeding Episodes | 2.0 Events per year |
Secondary
Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Target Joint Bleeding Episodes
Rate of treated spontaneous and traumatic target joint bleeding episodes for haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off
Population: FAS included all participants randomised to the new concizumab PPX dosing regimen or on-demand treatment after the treatment pause or allocated to arm 3 or 4 with the new concizumab PPX dosing regimen. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Target Joint Bleeding Episodes | 2.2 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous and Traumatic Target Joint Bleeding Episodes | 0.7 Events per year |
Secondary
Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous Bleeding Episodes
Rate of treated spontaneous bleeding episodes for haemophilia B participants without inhibitors is presented. The observation period used for reporting this endpoint is OTwoATexBR. It is defined as the time period after the restart where participants are treated by concizumab treatment or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleeding episode. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration after the pause or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From randomisation after the pause (week 0) up until start of concizumab treatment (week 24) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the 56 week cut-off
Population: FAS included all participants randomised to the new concizumab PPX dosing regimen or on-demand treatment after the treatment pause or allocated to arm 3 or 4 with the new concizumab PPX dosing regimen. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous On Demand (OnD) Treatment: No Prophylaxis (PPX) - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous Bleeding Episodes | 10.8 Events per year |
| Arm 2: Previous OnD Treatment: Concizumab PPX - Participants With HA | Haemophilia B Participants Without Inhibitors: Rate of Treated Spontaneous Bleeding Episodes | 1.0 Events per year |