Haemophilia A With Inhibitors, Haemophilia B With 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 with inhibitors. The purpose is to show that concizumab can prevent bleeds in the body and is safe to use. Participants who usually only take medicine to treat bleeds (on-demand) will be placed in one of two groups. In one group, participants will get study medicine from the start of the study. In the other group, participants will continue with their normal medicine and get study medicine after 6 months. Which treatment the participant gets is decided by chance. Participants who usually take medicine to prevent bleeds (prophylaxis treatment) or who are already being treated with concizumab (study medicine) will receive the study medicine from the start of the study. Participants will get 1 injection with the study medicine every day under the skin. This participants will have to do themselves and can be done at home. The study doctor will hand out the medicine in the form of a pen-injector. The pen-injector will contain the study medicine. The study will last for about seven years. The length of time the participants will be in the study depends on when they agreed to take part or when the medicine is available for purchase in their country (31 December 2026 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. Participants will be asked to record information into an electronic diary during the study and may also be asked to wear an activity tracker.
Interventions
DRUGConcizumab
Concizumab will be administered daily subcutaneously (s.c., under the skin). When patients are randomised to concizumab prophylaxis they will receive a loading dose of 1.0 mg/kg concizumab at visit 2a (week 0: arm 2, 3 \& 4) or visit 9a (week 24: arm 1) followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5-8-week dose adjustment period on 0.20 mg/kg concizumab, the patients can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 4a.1 (week 6: arm 2, 3 \& 4) or 9a.3 (week 30: arm 1) and will be based on the concizumab exposure level measured at the previous visit 4a (week 4) or 9a.2 (week 28). Patients who have concizumab exposure levels of 200-4000 ng/mL will stay at 0.20 mg/kg concizumab. Patients in arm 1 will continue on-demand treatment with their usual bypassing product until visit 9a (week 24: end of main part for arm 1).
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will be randomised to concizumab prophylaxis (ppx) or no ppx or assigned into non-randomised treatment arms, based on their treatment regimen before entering the trial. Main part of trial is completed when participant has completed at least 24 weeks of participation in arm 1 or 32 weeks in arms 2, 3 and 4. After main part, all participants will be offered to continue in extension part and receive treatment until concizumab is commercially available in their countries or until 31 December 2026 for up to 332 weeks (arms 1-4) or up to 324 weeks (randomised to arm 1 before the pause). After extension part, participant will enter safety follow-up part on visit 26a, which defines end-of-treatment. Participant will receive last dose of trial drug at home on day prior to visit 26a. On visit 26a, participants will either start up commercially available concizumab or revert to previous ppx schedule or on-demand regimen. Follow-up part will start on visit 26a and lasts for 7 weeks.
Eligibility
Sex/Gender
MALE
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 Haemophilia A or B of any severity with documented history of inhibitor (equal to or above 0.6 Bethesda Units (BU). * Patient has been prescribed, or in need of, treatment with bypassing agents in the last 24 weeks prior to screening (for patients not previously enrolled in NN7415-4310 (explorer 4)).
Exclusion criteria
* Known or suspected hypersensitivity to any constituent of the trial product or related products. * Known inherited or acquired coagulation disorder other than congenital haemophilia. * Ongoing or planned Immune Tolerance Induction treatment. * History of thromboembolic disease (includes arterial and venous thrombosis including myocardial infarction, pulmonary embolism, cerebral infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events and peripheral artery occlusion). Current clinical signs of, or treatment for thromboembolic disease. Patients who in the judgement of the investigator are considered at high risk of thromboembolic events (thromboembolic risk factors could include, but are not limited to, hypercholesterolemia, diabetes mellitus, hypertension, obesity, smoking, family history of thromboembolic events, arteriosclerosis, other conditions associated with increased risk of thromboembolic events.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Treated Spontaneous and Traumatic Bleeding Episodes | On demand (arm 1): From week 0 up until start of concizumab treatment (at least 24 weeks) Concizumab (arm 2): From week 0 up until the primary analysis cut-off (at least 32 weeks) | Rate of treated spontaneous and traumatic bleeding episodes is presented. The observation period used for reporting this endpoint is on-treatment without ancillary therapy excl. data on initial regimen for participants exposed to both regimens (OTwoATexIR). It is defined as the time period where participants are treated by either the new concizumab dosing regimen or the initial concizumab dosing regimen (only included if not exposed to the new concizumab dosing regimen) or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleed during any of the cases. The data is reported in the terms of annualised bleeding rate (ABR). Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Treated Spontaneous Bleeding Episodes | On demand (arm 1): From week 0 up until start of concizumab treatment (at least 24 weeks) Extension concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off Concizumab (arm 2): From week 0 up until week 56 cut-off | Rate of treated spontaneous bleeding episodes is presented. The observation period used for reporting this endpoint is OTwoATexIR. It is defined as the time period where participants are treated by either the new concizumab dosing regimen or the initial concizumab dosing regimen (only included if not exposed to the new concizumab dosing regimen) or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleed during any of the cases. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. |
| Rate of Treated Spontaneous and Traumatic Joint Bleeds | On demand (arm 1): From week 0 up until start of concizumab treatment (at least 24 weeks) Extension concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off Concizumab (arm 2): From week 0 up until week 56 cut-off | Rate of treated spontaneous and traumatic joint bleeds is presented. Observation period used for reporting this endpoint is OTwoATexIR. It is defined as time period where participants are treated by either the new concizumab dosing regimen or the initial concizumab dosing regimen (only included if not exposed to the new concizumab dosing regimen) or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleed during any of the cases. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. |
| Rate of Treated Spontaneous and Traumatic Target Joint Bleeds | On demand (arm 1): From week 0 up until start of concizumab treatment (at least 24 weeks) Extension concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off Concizumab (arm 2): From week 0 up until week 56 cut-off | Rate of treated spontaneous and traumatic target joint bleeds is presented. Observation period used for reporting the endpoint is OTwoATexIR. It is defined as time period where participants are treated by either the new concizumab dosing regimen or the initial concizumab dosing regimen (only included if not exposed to new concizumab dosing regimen) or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleed during any of the cases. The data is reported in terms of ABR. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen. |
| Change in 36-item Short Form Health Survey (SF-36v2) Bodily Pain | Baseline (week 0), Week 24 | Change in 36-item SF-36v2 bodily pain from baseline (week 0) to week 24 is presented. SF-36 v2 Health Survey is 36-item generic patient-reported outcome (PRO) instrument measuring health-related quality of life and general health status across disease areas. SF-36 v2 scores are norm-based scores, i.e. transformed to a scale where the 2009 US general population has a mean of 50 and an SD of 10. Lowest and highest scores for bodily pain are 21.68 to 62.0. Higher values indicate better functional health and well-being. Observation period for reporting the data is on-treatment without data on initial regimen (OTexIR) which is defined as time period where participants are considered affected by on demand treatment or treatment with new concizumab dosing regimen. Week 0 is defined as time of randomisation to on-demand administration or start of new concizumab dosing regimen. |
| Change in SF36v2 Physical Functioning | Baseline (week 0), Week 24 | Change in 36-item SF-36v2 physical functioning from baseline (week 0) to week 24 is presented. SF-36 v2 Health Survey is 36-item generic PRO instrument measuring health-related quality of life and general health status across disease areas. SF-36 v2 scores are norm-based scores, i.e. transformed to a scale where the 2009 US general population has a mean of 50 and an SD of 10. Lowest and highest scores for physical functioning are 19.26 to 57.54. Higher values indicate better functional health and well-being. Observation period used for reporting the data is OTexIR which is defined as time period where participants are considered affected by on demand treatment or treatment with new concizumab dosing regimen. Week 0 is defined as time of randomisation to on-demand administration or start of new concizumab dosing regimen. |
| Number of Thromboembolic Events | On demand (arm 1 ): From week 0 until start of concizumab treatment (atleast 24 weeks) Concizumab (arms 2-4): From week 0 up until week 56 cut-off Extension Concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off | Number of thromboembolic events is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment. |
| Number of Hypersensitivity Type Reactions | On demand (arm 1 ): From week 0 until start of concizumab treatment (atleast 24 weeks) Concizumab (arms 2-4): From week 0 up until week 56 cut-off Extension Concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off | Number of hypersensitivity type reactions is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment. |
| Number of Injection Site Reactions | On demand (arm 1 ): From week 0 until start of concizumab treatment (atleast 24 weeks) Concizumab (arms 2-4): From week 0 up until week 56 cut-off Extension Concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off | Number of injection site reactions is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment. |
| Number of Participants With Antibodies to Concizumab | Concizumab (arms 2-4): From week 0 up until week 56 cut-off Extension Concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off | Number of participants with antibodies to concizumab is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment. |
| Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | Pre-dose (prior to concizumab administration at week 56) | Pre-dose (trough) concizumab plasma concentration is presented. The observation period used for reporting the endpoint is OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen. |
| Pre-dose Thrombin Peak | Pre-dose (prior to concizumab administration at week 56) | Pre-dose thrombin peak for concizumab is presented. The observation period used for reporting the endpoint is OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen. |
| Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | Pre-dose (prior to concizumab administration at week 56) | Pre-dose free TFPI concentration for concizumab is presented. The observation period used for reporting the endpoint is OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen. |
| Maximum Concizumab Plasma Concentration (Cmax) | Week 24: Predose, 3 hours (h), 6h, 9h, 24h | Maximum concizumab plasma concentration is presented. The observation period used for reporting the endpoint is on OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen. |
| Area Under the Concizumab Plasma Concentration-time Curve (AUC) | Week 24: Predose, 3 hours (h), 6h, 9h, 24h | Area under the concizumab plasma concentration-time curve is presented. The observation period used for reporting the endpoint is OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen. |
Countries
Algeria, Australia, Austria, Bulgaria, Canada, Croatia, Czechia, Denmark, France, India, Italy, Japan, Malaysia, Mexico, Norway, Poland, Portugal, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, 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 in 27 countries. There were 70 sites that randomised participants. The details are as follows: Algeria (2), Australia (2), Austria (1), Bulgaria (1), Canada (0), Croatia (1), Czech Republic (1), Denmark (1), France (4), India (4), Italy (4), Japan (6), Republic of Korea (2), Malaysia (3), Mexico (1), Poland (4), Portugal (1), Russian Federation (5), Serbia (1), South Africa (2), Spain (5), Sweden (1), Thailand (3), Turkey (4), Ukraine (2), UK (3), United States (6).
Pre-assignment details
133 participants were actually randomised for the study. The data presented in the results form is till the 56 week cut off (except the data for primary outcome measure, patient reported outcome measures, maximum concizumab plasma concentration and area under the concizumab plasma concentration-time curve) as the study is still ongoing with the extension phase.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Previous on Demand: No Prophylaxis Participants with hemophilia A with inhibitor (HAwI) and hemophilia B with inhibitor (HAwB) received their on-demand treatment for a minimum of 24 weeks. 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. | 19 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) Participants with HAwI and HBwI 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. | 29 |
| Arm 3: Concizumab Non-naive: Concizumab PPX Participants with HAwI and HBwI received a loading dose (participants entering from the phase 2 trial \[N7415-4310\] 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. | 15 |
| Arm 4: Concizumab Naive: Concizumab PPX Participants with HAwI and HBwI 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. | 55 |
| Total | 118 |
Baseline characteristics
| Characteristic | Arm 1: Previous on Demand: No Prophylaxis | Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Arm 3: Concizumab Non-naive: Concizumab PPX | Arm 4: Concizumab Naive: Concizumab PPX | Total |
|---|---|---|---|---|---|
| Age, Continuous | 32.3 Years STANDARD_DEVIATION 17.6 | 24.8 Years STANDARD_DEVIATION 14.4 | 35.1 Years STANDARD_DEVIATION 10 | 26.4 Years STANDARD_DEVIATION 11.5 | 28.1 Years STANDARD_DEVIATION 13.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 0 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 25 Participants | 15 Participants | 52 Participants | 108 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 13 Participants | 4 Participants | 12 Participants | 35 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 0 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) White | 9 Participants | 9 Participants | 11 Participants | 38 Participants | 67 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 19 Participants | 29 Participants | 15 Participants | 55 Participants | 118 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 19 | 0 / 13 | 4 / 33 | 1 / 21 | 1 / 60 |
| other Total, other adverse events | 8 / 19 | 8 / 13 | 15 / 33 | 13 / 21 | 35 / 60 |
| serious Total, serious adverse events | 3 / 19 | 2 / 13 | 9 / 33 | 2 / 21 | 9 / 60 |
Outcome results
Primary
Rate of Treated Spontaneous and Traumatic Bleeding Episodes
Rate of treated spontaneous and traumatic bleeding episodes is presented. The observation period used for reporting this endpoint is on-treatment without ancillary therapy excl. data on initial regimen for participants exposed to both regimens (OTwoATexIR). It is defined as the time period where participants are treated by either the new concizumab dosing regimen or the initial concizumab dosing regimen (only included if not exposed to the new concizumab dosing regimen) or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleed during any of the cases. The data is reported in the terms of annualised bleeding rate (ABR). Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From week 0 up until start of concizumab treatment (at least 24 weeks) Concizumab (arm 2): From week 0 up until the primary analysis cut-off (at least 32 weeks)
Population: Full analysis set (FAS) included all participants randomised to concizumab prophylaxis (PPX) or on-demand treatment or allocated to arms 3 or 4. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 9.8 Events per year |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Rate of Treated Spontaneous and Traumatic Bleeding Episodes | 0.0 Events per year |
p-value: <0.00195% CI: [0.07, 0.29]Two-sided test of no difference from 1
Secondary
Area Under the Concizumab Plasma Concentration-time Curve (AUC)
Area under the concizumab plasma concentration-time curve is presented. The observation period used for reporting the endpoint is OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen.
Time frame: Week 24: Predose, 3 hours (h), 6h, 9h, 24h
Population: SAS included all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analyzed = participants with available data for this outcome measure. This endpoint is applicable for reported arms only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Area Under the Concizumab Plasma Concentration-time Curve (AUC) | 25991.5 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 17069.7 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Area Under the Concizumab Plasma Concentration-time Curve (AUC) | 47149.3 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 38192.8 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Area Under the Concizumab Plasma Concentration-time Curve (AUC) | 32903.5 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 32741.2 |
Secondary
Change in 36-item Short Form Health Survey (SF-36v2) Bodily Pain
Change in 36-item SF-36v2 bodily pain from baseline (week 0) to week 24 is presented. SF-36 v2 Health Survey is 36-item generic patient-reported outcome (PRO) instrument measuring health-related quality of life and general health status across disease areas. SF-36 v2 scores are norm-based scores, i.e. transformed to a scale where the 2009 US general population has a mean of 50 and an SD of 10. Lowest and highest scores for bodily pain are 21.68 to 62.0. Higher values indicate better functional health and well-being. Observation period for reporting the data is on-treatment without data on initial regimen (OTexIR) which is defined as time period where participants are considered affected by on demand treatment or treatment with new concizumab dosing regimen. Week 0 is defined as time of randomisation to on-demand administration or start of new concizumab dosing regimen.
Time frame: Baseline (week 0), Week 24
Population: FAS included all participants randomised to concizumab prophylaxis (PPX) or on-demand treatment or allocated to arms 3 or 4. Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Change in 36-item Short Form Health Survey (SF-36v2) Bodily Pain | 3.2 Score on a scale | Standard Deviation 10.1 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Change in 36-item Short Form Health Survey (SF-36v2) Bodily Pain | 9.3 Score on a scale | Standard Deviation 9.2 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Change in 36-item Short Form Health Survey (SF-36v2) Bodily Pain | 4.3 Score on a scale | Standard Deviation 10.1 |
| Arm 4: Concizumab Naive: Concizumab PPX | Change in 36-item Short Form Health Survey (SF-36v2) Bodily Pain | 6.5 Score on a scale | Standard Deviation 10 |
Secondary
Change in SF36v2 Physical Functioning
Change in 36-item SF-36v2 physical functioning from baseline (week 0) to week 24 is presented. SF-36 v2 Health Survey is 36-item generic PRO instrument measuring health-related quality of life and general health status across disease areas. SF-36 v2 scores are norm-based scores, i.e. transformed to a scale where the 2009 US general population has a mean of 50 and an SD of 10. Lowest and highest scores for physical functioning are 19.26 to 57.54. Higher values indicate better functional health and well-being. Observation period used for reporting the data is OTexIR which is defined as time period where participants are considered affected by on demand treatment or treatment with new concizumab dosing regimen. Week 0 is defined as time of randomisation to on-demand administration or start of new concizumab dosing regimen.
Time frame: Baseline (week 0), Week 24
Population: FAS included all participants randomised to concizumab prophylaxis (PPX) or on-demand treatment or allocated to arms 3 or 4. Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Change in SF36v2 Physical Functioning | 1.6 Score on a scale | Standard Deviation 10.9 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Change in SF36v2 Physical Functioning | 3.1 Score on a scale | Standard Deviation 6.2 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Change in SF36v2 Physical Functioning | 3.8 Score on a scale | Standard Deviation 8.7 |
| Arm 4: Concizumab Naive: Concizumab PPX | Change in SF36v2 Physical Functioning | 4.9 Score on a scale | Standard Deviation 6.7 |
Secondary
Maximum Concizumab Plasma Concentration (Cmax)
Maximum concizumab plasma concentration is presented. The observation period used for reporting the endpoint is on OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen.
Time frame: Week 24: Predose, 3 hours (h), 6h, 9h, 24h
Population: SAS included all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analyzed = participants with available data for this outcome measure. This endpoint is applicable for reported arms only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Maximum Concizumab Plasma Concentration (Cmax) | 992.2 ng/mL | Geometric Coefficient of Variation 1 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Maximum Concizumab Plasma Concentration (Cmax) | 1514.1 ng/mL | Geometric Coefficient of Variation 1.7 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Maximum Concizumab Plasma Concentration (Cmax) | 1153.0 ng/mL | Geometric Coefficient of Variation 1.3 |
Secondary
Number of Hypersensitivity Type Reactions
Number of hypersensitivity type reactions is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment.
Time frame: From week 0 to end of trial (week 167)
Secondary
Number of Hypersensitivity Type Reactions
Number of hypersensitivity type reactions is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment.
Time frame: On demand (arm 1 ): From week 0 until start of concizumab treatment (atleast 24 weeks) Concizumab (arms 2-4): From week 0 up until week 56 cut-off Extension Concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off
Population: SAS included all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Number of Hypersensitivity Type Reactions | 0 Reactions |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Number of Hypersensitivity Type Reactions | 0 Reactions |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Number of Hypersensitivity Type Reactions | 1 Reactions |
| Arm 4: Concizumab Naive: Concizumab PPX | Number of Hypersensitivity Type Reactions | 0 Reactions |
| Arm 4: Concizumab Naive: Concizumab PPX | Number of Hypersensitivity Type Reactions | 1 Reactions |
Secondary
Number of Injection Site Reactions
Number of injection site reactions is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment.
Time frame: From week 0 to end of trial (week 167)
Secondary
Number of Injection Site Reactions
Number of injection site reactions is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment.
Time frame: On demand (arm 1 ): From week 0 until start of concizumab treatment (atleast 24 weeks) Concizumab (arms 2-4): From week 0 up until week 56 cut-off Extension Concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off
Population: SAS included all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Number of Injection Site Reactions | 0 Reactions |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Number of Injection Site Reactions | 1 Reactions |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Number of Injection Site Reactions | 11 Reactions |
| Arm 4: Concizumab Naive: Concizumab PPX | Number of Injection Site Reactions | 5 Reactions |
| Arm 4: Concizumab Naive: Concizumab PPX | Number of Injection Site Reactions | 43 Reactions |
Secondary
Number of Participants With Antibodies to Concizumab
Number of participants with antibodies to concizumab is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment.
Time frame: From week 0 to end of trial (week 167)
Secondary
Number of Participants With Antibodies to Concizumab
Number of participants with antibodies to concizumab is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment.
Time frame: Concizumab (arms 2-4): From week 0 up until week 56 cut-off Extension Concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off
Population: SAS included all participants exposed to concizumab PPX or randomised to on-demand treatment. The data is presented in a combined manner across all Concizumab PPX arms (arm 2-4) and extension part of concizumab (arm 1) considering that the trial is still ongoing, and that incidence of immunogenicity can still change when the trial is completed, hence it was decided to provide now only total incidence. A more granular picture of immunogenicity per arm, will be provided once trial is finished.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Number of Participants With Antibodies to Concizumab | 35 Participants |
Secondary
Number of Thromboembolic Events
Number of thromboembolic events is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment.
Time frame: On demand (arm 1 ): From week 0 until start of concizumab treatment (atleast 24 weeks) Concizumab (arms 2-4): From week 0 up until week 56 cut-off Extension Concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off
Population: Safety analysis set (SAS) included all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Number of Thromboembolic Events | 0 Events |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Number of Thromboembolic Events | 0 Events |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Number of Thromboembolic Events | 1 Events |
| Arm 4: Concizumab Naive: Concizumab PPX | Number of Thromboembolic Events | 0 Events |
| Arm 4: Concizumab Naive: Concizumab PPX | Number of Thromboembolic Events | 0 Events |
Secondary
Number of Thromboembolic Events
Number of thromboembolic events is presented. The observation period used for reporting the endpoint is on-treatment period which is defined as the time period where participants are considered to be affected by on-demand treatment or concizumab treatment.
Time frame: From week 0 to end of trial (week 167)
Secondary
Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration
Pre-dose free TFPI concentration for concizumab is presented. The observation period used for reporting the endpoint is OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen.
Time frame: Pre-dose (prior to concizumab administration at week 56)
Population: SAS included all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analyzed = participants with available data for this outcome measure. The endpoint is applicable for reported arms (extension part arm 1, arm 2, arm 3 and arm 4) only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 13.2 ng/mL | Geometric Coefficient of Variation 106.4 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 15.2 ng/mL | Geometric Coefficient of Variation 108.7 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 12.1 ng/mL | Geometric Coefficient of Variation 123 |
| Arm 4: Concizumab Naive: Concizumab PPX | Pre-dose Free Tissue Factor Pathway Inhibitor (TFPI) Concentration | 11.0 ng/mL | Geometric Coefficient of Variation 95.6 |
Secondary
Pre-dose Thrombin Peak
Pre-dose thrombin peak for concizumab is presented. The observation period used for reporting the endpoint is OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen.
Time frame: Pre-dose (prior to concizumab administration at week 56)
Population: SAS included all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analyzed = participants with available data for this outcome measure. The endpoint is applicable for reported arms (extension part arm 1, arm 2, arm 3 and arm 4) only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Pre-dose Thrombin Peak | 104.2 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 39 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Pre-dose Thrombin Peak | 67.3 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 88.7 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Pre-dose Thrombin Peak | 76.2 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 78.6 |
| Arm 4: Concizumab Naive: Concizumab PPX | Pre-dose Thrombin Peak | 75.3 nanomoles per liter (nmol/L) | Geometric Coefficient of Variation 43.1 |
Secondary
Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough)
Pre-dose (trough) concizumab plasma concentration is presented. The observation period used for reporting the endpoint is OTexIR. It is defined as the time period where participants are considered to be affected by on demand treatment or treatment with the new concizumab dosing regimen.
Time frame: Pre-dose (prior to concizumab administration at week 56)
Population: SAS included all participants exposed to concizumab PPX or randomised to on-demand treatment. Overall number of participants analyzed = participants with available data for this outcome measure. The endpoint is applicable for reported arms (extension part arm 1, arm 2, arm 3 and arm 4) only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | 808.7 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 263.4 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | 570.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 225.7 |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | 590.6 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 600.9 |
| Arm 4: Concizumab Naive: Concizumab PPX | Pre-dose (Trough) Concizumab Plasma Concentration (Ctrough) | 717.3 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 328.5 |
Secondary
Rate of Treated Spontaneous and Traumatic Joint Bleeds
Rate of treated spontaneous and traumatic joint bleeds is presented. Observation period used for reporting this endpoint is OTwoATexIR. It is defined as time period where participants are treated by either the new concizumab dosing regimen or the initial concizumab dosing regimen (only included if not exposed to the new concizumab dosing regimen) or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleed during any of the cases. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From week 0 up until start of concizumab treatment (at least 24 weeks) Extension concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off Concizumab (arm 2): From week 0 up until week 56 cut-off
Population: FAS included all participants randomised to concizumab prophylaxis (PPX) or on-demand treatment or allocated to arms 3 or 4. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Rate of Treated Spontaneous and Traumatic Joint Bleeds | 6.5 Events per year |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Rate of Treated Spontaneous and Traumatic Joint Bleeds | 1.3 Events per year |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Rate of Treated Spontaneous and Traumatic Joint Bleeds | 0.7 Events per year |
Secondary
Rate of Treated Spontaneous and Traumatic Target Joint Bleeds
Rate of treated spontaneous and traumatic target joint bleeds is presented. Observation period used for reporting the endpoint is OTwoATexIR. It is defined as time period where participants are treated by either the new concizumab dosing regimen or the initial concizumab dosing regimen (only included if not exposed to new concizumab dosing regimen) or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleed during any of the cases. The data is reported in terms of ABR. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From week 0 up until start of concizumab treatment (at least 24 weeks) Extension concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off Concizumab (arm 2): From week 0 up until week 56 cut-off
Population: FAS included all participants randomised to concizumab prophylaxis (PPX) or on-demand treatment or allocated to arms 3 or 4. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Rate of Treated Spontaneous and Traumatic Target Joint Bleeds | 0.0 Events per year |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Rate of Treated Spontaneous and Traumatic Target Joint Bleeds | 0.0 Events per year |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Rate of Treated Spontaneous and Traumatic Target Joint Bleeds | 0.0 Events per year |
Secondary
Rate of Treated Spontaneous Bleeding Episodes
Rate of treated spontaneous bleeding episodes is presented. The observation period used for reporting this endpoint is OTwoATexIR. It is defined as the time period where participants are treated by either the new concizumab dosing regimen or the initial concizumab dosing regimen (only included if not exposed to the new concizumab dosing regimen) or are treated by on-demand treatment and additionally have not used factor-containing products not related to treatment of a bleed during any of the cases. The data is reported in the terms of ABR. Week 0 is defined as time of randomisation to on-demand administration or time of start of the new concizumab dosing regimen.
Time frame: On demand (arm 1): From week 0 up until start of concizumab treatment (at least 24 weeks) Extension concizumab (arm 1): From start of new concizumab dosing regimen (week 25) up until week 56 cut-off Concizumab (arm 2): From week 0 up until week 56 cut-off
Population: FAS included all participants randomised to concizumab prophylaxis (PPX) or on-demand treatment or allocated to arms 3 or 4. This endpoint is only defined for arms 1 and 2 as per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Previous on Demand: No Prophylaxis | Rate of Treated Spontaneous Bleeding Episodes | 8.4 Events per year |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Rate of Treated Spontaneous Bleeding Episodes | 0.0 Events per year |
| Arm 2: Previous on Demand: Concizumab Prophylaxis (PPX) | Rate of Treated Spontaneous Bleeding Episodes | 0.0 Events per year |