Congenital Bleeding Disorder, Haemophilia A With Inhibitors, Haemophilia B With Inhibitors
Conditions
Brief summary
This trial is conducted in Africa, Asia, Europe and North America. The aim of the trial is to assess the efficacy of concizumab administered s.c. (subcutaneously, under the skin) once daily in preventing bleeding episodes in haemophilia A and B patients with inhibitors.
Interventions
DRUGConcizumab
A loading dose of 0.5 mg/kg will be given as the first dose, followed by 0.15 mg/kg (with potential stepwise dose escalation to 0.25 mg/kg) administered daily s.c. (subcutaneously, under the skin). Treatment duration is 24 weeks in the main trial, and up to 52 weeks in the extension phase
DRUGEptacog alfa
A single dose of 90 μg/kg eptacog alfa one week after dosing with concizumab. On-demand treatment during bleeding episodes in both treatment arms
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 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 the suitability for the trial - Male haemophilia A or B patients with inhibitors aged 18 years or older at the time of signing informed consent - Patients currently in need of treatment with bypassing agents
Exclusion criteria
- Known or suspected hypersensitivity to trial product(s) or related products - Known inherited or acquired bleeding disorder other than haemophilia - Ongoing or planned immune tolerance induction therapy or prophylaxis with FVIII or FIX
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Bleeding Episodes | During at least 24 weeks from treatment onset (week 0) | The number of bleeding episodes that were treated during at least 24 weeks from treatment onset (week 0) are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Spontaneous Bleeding Episodes | During at least 24 weeks from treatment onset (week 0) | Bleeds that were not linked to a specific, known action or event are called spontaneous bleeding episodes. The number of spontaneous bleeding episodes that were treated during at least 24 weeks from treatment onset (week 0) are presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Number of Treatment-emergent Adverse Events (TEAEs) During at Least 24 Weeks From Treatment Onset | During at least 24 weeks from treatment onset (week 0) | An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred during at least 24 weeks from treatment onset (week 0) are presented. The data is presented per the dose level which the participants have reached at the time of event. |
| Number of Treatment-emergent Adverse Events (TEAEs) During at Least 76 Weeks From Treatment Onset | During at least 76 weeks from treatment onset (week 0) | An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred during at least 76 weeks from treatment onset (week 0) are presented. The data is presented per the dose level which the participants have reached at the time of event. |
| Number of Treatment-emergent Adverse Events (TEAEs) Within 24 Hours After Eptacog Alfa Administration | Within 24 hours after eptacog alfa administration | An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred within 24 hours after eptacog alfa administration are presented. This outcome measure is applicable only for 'Eptacog alfa' treatment arm. |
| Occurrence of Anti-concizumab Antibodies During at Least 24 Weeks From Treatment Onset | During at least 24 weeks from treatment onset (week 0) | Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset (week 0) is presented. This outcome measure is applicable for only 'Concizumab' treatment arm. |
| Occurrence of Anti-concizumab Antibodies During at Least 76 Weeks From Treatment Onset | During at least 76 weeks from treatment onset (week 0) | Occurrence of anti-concizumab antibodies during at least 76 weeks from treatment onset (week 0) is presented. This outcome measure is applicable for only 'Concizumab' treatment arm. |
| Change in Fibrinogen | During at least 24 weeks from treatment onset (week 0) | Change in fibrinogen during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Change in D-dimer | During at least 24 weeks from treatment onset (week 0) | Change in D-dimer during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| The Number of Bleeding Episodes | During at least 76 weeks from treatment onset (week 0) | The number of bleeding episodes that were treated during at least 76 weeks from treatment onset (week 0) are presented. This outcome measure is applicable for only 'Concizumab' treatment arm. |
| Change in Prothrombin Time (PT) | During at least 24 weeks from treatment onset (week 0) | Change in PT during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Change in Activated Partial Thromboplastin Time (APTT) | During at least 24 weeks from treatment onset (week 0) | Change in APTT during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Change in Anti-thrombin (AT) | During at least 24 weeks from treatment onset (week 0) | Change in AT during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Concentration of Concizumab | Prior to the last dose administration at 24 weeks | Concentration of concizumab prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value | Prior to the last dose administration at 24 weeks | Free TFPI (TFPI not bound to concizumab) concentration value prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Peak Thrombin Generation | Prior to the last dose administration at 24 weeks | Peak thrombin generation is the maximal concentration of thrombin formed at a given point in time. Peak thrombin generation prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Endogenous Thrombin Potential | Prior to the last dose administration at 24 weeks | Endogenous thrombin potential prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Thrombin Generation Velocity Index | Prior to the last dose administration at 24 weeks | Thrombin generation velocity index prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
| Change in Prothrombin Fragment 1 + 2 (F1 + 2) | During at least 24 weeks from treatment onset (week 0) | Change in F1 + 2 during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment. |
Countries
Austria, Canada, Croatia, Denmark, Greece, Israel, Italy, Japan, Malaysia, Spain, Sweden, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 17 sites in 12 countries as follows: Austria (1), Croatia (1), Denmark (1), Italy (2), Spain (2), Sweden (1), the United Kingdom (1), Israel (1), Malaysia (2), Ukraine (1), Japan (2) and the United States (2). In addition to these sites, 4 sites were approved by the IRB/IEC and/or local health authority but did not screen or assign any participants to treatment.
Pre-assignment details
The trial consisted of two treatment periods: main part which lasted 24 weeks for participants randomised to eptacog alfa and at least 24 weeks for participants randomised to concizumab, and an extension part which lasted up to 94 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Concizumab Participants were to receive subcutaneous (s.c.) injection of concizumab once daily. In main part, the initial dose was 0.15 milligrams per kilogram (mg/kg) and then the dose was escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. Participants who completed the main part of the study continued their treatment in the extension part for 52-94 weeks. A loading dose of 0.5 mg/kg was given as the first concizumab dose. A single injection of 90 micrograms per kilogram (μg/kg) eptacog alfa (rFVIIa) was administered in a non-bleeding state one week after dosing with concizumab had initiated. | 17 |
| Eptacog Alfa Participants were to receive eptacog alfa on-demand treatment for 24 weeks in main part. All participants were then switched to concizumab treatment in the extension part. | 9 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extension Part | Lack of Efficacy | 0 | 0 | 1 |
| Extension Part | Physician Decision | 0 | 0 | 1 |
| Extension Part | Withdrawal by Subject | 0 | 0 | 1 |
| Main Part | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Eptacog Alfa | Total | Concizumab |
|---|---|---|---|
| Age, Continuous | 41.1 Years STANDARD_DEVIATION 15 | 36.5 Years STANDARD_DEVIATION 12.7 | 34.1 Years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 25 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 20 Participants | 15 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 26 Participants | 17 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 17 | 0 / 2 | 0 / 23 | 0 / 13 | 0 / 4 |
| other Total, other adverse events | 7 / 9 | 13 / 17 | 2 / 2 | 13 / 23 | 9 / 13 | 2 / 4 |
| serious Total, serious adverse events | 3 / 9 | 1 / 17 | 0 / 2 | 3 / 23 | 1 / 13 | 0 / 4 |
Outcome results
Primary
The Number of Bleeding Episodes
The number of bleeding episodes that were treated during at least 24 weeks from treatment onset (week 0) are presented.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The FAS included all randomised participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concizumab- Main Part | The Number of Bleeding Episodes | 47 episodes |
| Eptacog Alfa- Main Part | The Number of Bleeding Episodes | 77 episodes |
Secondary
Change in Activated Partial Thromboplastin Time (APTT)
Change in APTT during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Activated Partial Thromboplastin Time (APTT) | -2.6 sec | Standard Deviation 12.1 |
| Eptacog Alfa- Main Part | Change in Activated Partial Thromboplastin Time (APTT) | 0.9 sec | Standard Deviation 2.3 |
| Eptacog Alfa- Main Part | Change in Activated Partial Thromboplastin Time (APTT) | 5.9 sec | Standard Deviation 15.2 |
Secondary
Change in Activated Partial Thromboplastin Time (APTT)
Change in APTT during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 76 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Activated Partial Thromboplastin Time (APTT) | -6.6 sec | Standard Deviation 9 |
| Eptacog Alfa- Main Part | Change in Activated Partial Thromboplastin Time (APTT) | 3.7 sec | Standard Deviation 6.9 |
| Eptacog Alfa- Main Part | Change in Activated Partial Thromboplastin Time (APTT) | 20.9 sec | Standard Deviation 17.3 |
Secondary
Change in Anti-thrombin (AT)
Change in AT after at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: After at least 76 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Anti-thrombin (AT) | -3 Percentage point of AT | Standard Deviation 15 |
| Eptacog Alfa- Main Part | Change in Anti-thrombin (AT) | -5 Percentage point of AT | Standard Deviation 11 |
| Eptacog Alfa- Main Part | Change in Anti-thrombin (AT) | -1 Percentage point of AT | Standard Deviation 14 |
Secondary
Change in Anti-thrombin (AT)
Change in AT during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Anti-thrombin (AT) | -1 Percentage point of AT | Standard Deviation 11 |
| Eptacog Alfa- Main Part | Change in Anti-thrombin (AT) | 8 Percentage point of AT | Standard Deviation 4 |
| Eptacog Alfa- Main Part | Change in Anti-thrombin (AT) | 1 Percentage point of AT | Standard Deviation 10 |
Secondary
Change in D-dimer
Change in D-dimer during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 76 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in D-dimer | 308 ng/mL | Standard Deviation 601 |
| Eptacog Alfa- Main Part | Change in D-dimer | 193 ng/mL | Standard Deviation 912 |
| Eptacog Alfa- Main Part | Change in D-dimer | 340 ng/mL | Standard Deviation 887 |
Secondary
Change in D-dimer
Change in D-dimer during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in D-dimer | 227 Nanograms per milliliter (ng/mL) | Standard Deviation 239 |
| Eptacog Alfa- Main Part | Change in D-dimer | 550 Nanograms per milliliter (ng/mL) | Standard Deviation 608 |
| Eptacog Alfa- Main Part | Change in D-dimer | -48 Nanograms per milliliter (ng/mL) | Standard Deviation 614 |
Secondary
Change in Fibrinogen
Change in fibrinogen during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 76 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Fibrinogen | -0.14 g/L | Standard Deviation 0.51 |
| Eptacog Alfa- Main Part | Change in Fibrinogen | -0.56 g/L | Standard Deviation 0.72 |
| Eptacog Alfa- Main Part | Change in Fibrinogen | -1.51 g/L | Standard Deviation 1.44 |
Secondary
Change in Fibrinogen
Change in fibrinogen during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Fibrinogen | -0.24 Grams per liter (g/L) | Standard Deviation 0.45 |
| Eptacog Alfa- Main Part | Change in Fibrinogen | -1.24 Grams per liter (g/L) | Standard Deviation 1.61 |
| Eptacog Alfa- Main Part | Change in Fibrinogen | 0.13 Grams per liter (g/L) | Standard Deviation 0.48 |
Secondary
Change in Prothrombin Fragment 1 + 2 (F1 + 2)
Change in F1 + 2 during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 76 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Prothrombin Fragment 1 + 2 (F1 + 2) | 159 pmol/L | Standard Deviation 202 |
| Eptacog Alfa- Main Part | Change in Prothrombin Fragment 1 + 2 (F1 + 2) | 457 pmol/L | Standard Deviation 458 |
| Eptacog Alfa- Main Part | Change in Prothrombin Fragment 1 + 2 (F1 + 2) | 349 pmol/L | Standard Deviation 452 |
Secondary
Change in Prothrombin Fragment 1 + 2 (F1 + 2)
Change in F1 + 2 during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Prothrombin Fragment 1 + 2 (F1 + 2) | 154 Picomoles per liter (pmol/L) | Standard Deviation 256 |
| Eptacog Alfa- Main Part | Change in Prothrombin Fragment 1 + 2 (F1 + 2) | 164 Picomoles per liter (pmol/L) | Standard Deviation 1 |
| Eptacog Alfa- Main Part | Change in Prothrombin Fragment 1 + 2 (F1 + 2) | 0 Picomoles per liter (pmol/L) | Standard Deviation 33 |
Secondary
Change in Prothrombin Time (PT)
Change in PT during at least 24 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Prothrombin Time (PT) | 0.2 Seconds (sec) | Standard Deviation 0.4 |
| Eptacog Alfa- Main Part | Change in Prothrombin Time (PT) | -1.0 Seconds (sec) | Standard Deviation 1 |
| Eptacog Alfa- Main Part | Change in Prothrombin Time (PT) | 0.0 Seconds (sec) | Standard Deviation 0.5 |
Secondary
Change in Prothrombin Time (PT)
Change in PT during at least 76 weeks from treatment onset (week 0) is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 76 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Change in Prothrombin Time (PT) | -0.4 sec | Standard Deviation 0.6 |
| Eptacog Alfa- Main Part | Change in Prothrombin Time (PT) | 0.4 sec | Standard Deviation 0.6 |
| Eptacog Alfa- Main Part | Change in Prothrombin Time (PT) | 0.3 sec | Standard Deviation 0.5 |
Secondary
Concentration of Concizumab
Concentration of concizumab prior to the last dose administration after atleast 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration after atleast 76 weeks
Population: The FAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Concentration of Concizumab | 205.5 ng/mL | Standard Deviation 254.5 |
| Eptacog Alfa- Main Part | Concentration of Concizumab | 1354.7 ng/mL | Standard Deviation 1004.3 |
| Eptacog Alfa- Main Part | Concentration of Concizumab | 941.7 ng/mL | Standard Deviation 943.1 |
Secondary
Concentration of Concizumab
Concentration of concizumab prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration at 24 weeks
Population: The FAS included all randomised participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Concentration of Concizumab | 350.6 ng/mL | Standard Deviation 316.8 |
| Eptacog Alfa- Main Part | Concentration of Concizumab | 517.5 ng/mL | Standard Deviation 309 |
Secondary
Endogenous Thrombin Potential
Endogenous thrombin potential prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration at 24 weeks
Population: The FAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Endogenous Thrombin Potential | 901.5 Nanomolar*minute (nM*min) | Standard Deviation 347.6 |
| Eptacog Alfa- Main Part | Endogenous Thrombin Potential | 1589.5 Nanomolar*minute (nM*min) | Standard Deviation 133.6 |
| Eptacog Alfa- Main Part | Endogenous Thrombin Potential | 228.0 Nanomolar*minute (nM*min) | — |
Secondary
Endogenous Thrombin Potential
Endogenous thrombin potential prior to the last dose administration after at least 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration after atleast 76 weeks
Population: The FAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Endogenous Thrombin Potential | 1056.5 nM*min | Standard Deviation 438.5 |
| Eptacog Alfa- Main Part | Endogenous Thrombin Potential | 1356.9 nM*min | Standard Deviation 223.9 |
| Eptacog Alfa- Main Part | Endogenous Thrombin Potential | 1178.0 nM*min | Standard Deviation 184.3 |
Secondary
Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value
Free TFPI (TFPI not bound to concizumab) concentration value prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration at 24 weeks
Population: The FAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value | 29.9 ng/mL | Standard Deviation 9.6 |
| Eptacog Alfa- Main Part | Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value | 4.8 ng/mL | Standard Deviation 0 |
| Eptacog Alfa- Main Part | Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value | 94.3 ng/mL | Standard Deviation 13.8 |
Secondary
Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value
Free TFPI concentration value prior to the last dose administration after atleast 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration after atleast 76 weeks
Population: The FAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value | 30.3 ng/mL | Standard Deviation 28.2 |
| Eptacog Alfa- Main Part | Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value | 8.3 ng/mL | Standard Deviation 4.9 |
| Eptacog Alfa- Main Part | Free Tissue Factor Pathway Inhibitor (TFPI) Concentration Value | 12.2 ng/mL | Standard Deviation 12.9 |
Secondary
Number of Treatment-emergent Adverse Events (TEAEs) During at Least 24 Weeks From Treatment Onset
An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred during at least 24 weeks from treatment onset (week 0) are presented. The data is presented per the dose level which the participants have reached at the time of event.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The safety analysis set (SAS) included all randomised participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concizumab- Main Part | Number of Treatment-emergent Adverse Events (TEAEs) During at Least 24 Weeks From Treatment Onset | 39 events |
| Eptacog Alfa- Main Part | Number of Treatment-emergent Adverse Events (TEAEs) During at Least 24 Weeks From Treatment Onset | 4 events |
| Eptacog Alfa- Main Part | Number of Treatment-emergent Adverse Events (TEAEs) During at Least 24 Weeks From Treatment Onset | 18 events |
Secondary
Number of Treatment-emergent Adverse Events (TEAEs) During at Least 76 Weeks From Treatment Onset
An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred during at least 76 weeks from treatment onset (week 0) are presented. The data is presented per the dose level which the participants have reached at the time of event.
Time frame: During at least 76 weeks from treatment onset (week 0)
Population: The SAS included all randomised participants. Overall number of participants analysed = number of participants contributed to the analysis at the particular dose level.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concizumab- Main Part | Number of Treatment-emergent Adverse Events (TEAEs) During at Least 76 Weeks From Treatment Onset | 104 events |
| Eptacog Alfa- Main Part | Number of Treatment-emergent Adverse Events (TEAEs) During at Least 76 Weeks From Treatment Onset | 24 events |
| Eptacog Alfa- Main Part | Number of Treatment-emergent Adverse Events (TEAEs) During at Least 76 Weeks From Treatment Onset | 3 events |
Secondary
Number of Treatment-emergent Adverse Events (TEAEs) Within 24 Hours After Eptacog Alfa Administration
An adverse event (AE) was any untoward medical occurrence in a participant administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred within 24 hours after eptacog alfa administration are presented. This outcome measure is applicable only for 'Eptacog alfa' treatment arm.
Time frame: Within 24 hours after eptacog alfa administration
Population: The SAS included all randomised participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concizumab- Main Part | Number of Treatment-emergent Adverse Events (TEAEs) Within 24 Hours After Eptacog Alfa Administration | 0 events |
Secondary
Occurrence of Anti-concizumab Antibodies During at Least 24 Weeks From Treatment Onset
Occurrence of anti-concizumab antibodies during at least 24 weeks from treatment onset (week 0) is presented. This outcome measure is applicable for only 'Concizumab' treatment arm.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The FAS included all participants who received concizumab.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Concizumab- Main Part | Occurrence of Anti-concizumab Antibodies During at Least 24 Weeks From Treatment Onset | Yes | 3 Participants |
| Concizumab- Main Part | Occurrence of Anti-concizumab Antibodies During at Least 24 Weeks From Treatment Onset | No | 14 Participants |
Secondary
Occurrence of Anti-concizumab Antibodies During at Least 76 Weeks From Treatment Onset
Occurrence of anti-concizumab antibodies during at least 76 weeks from treatment onset (week 0) is presented. This outcome measure is applicable for only 'Concizumab' treatment arm.
Time frame: During at least 76 weeks from treatment onset (week 0)
Population: The FAS included all participants who received concizumab.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Concizumab- Main Part | Occurrence of Anti-concizumab Antibodies During at Least 76 Weeks From Treatment Onset | Yes | 6 Participants |
| Concizumab- Main Part | Occurrence of Anti-concizumab Antibodies During at Least 76 Weeks From Treatment Onset | No | 19 Participants |
Secondary
Peak Thrombin Generation
Peak thrombin generation is the maximal concentration of thrombin formed at a given point in time. Peak thrombin generation prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration at 24 weeks
Population: The FAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Peak Thrombin Generation | 57.8 Nanomoles per liter (nmol/L) | Standard Deviation 28.9 |
| Eptacog Alfa- Main Part | Peak Thrombin Generation | 119.0 Nanomoles per liter (nmol/L) | Standard Deviation 12.7 |
| Eptacog Alfa- Main Part | Peak Thrombin Generation | 12.0 Nanomoles per liter (nmol/L) | — |
Secondary
Peak Thrombin Generation
Peak thrombin generation is the maximal concentration of thrombin formed at a given point in time. Peak thrombin generation prior to the last dose administration after atleast 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration after atleast 76 weeks
Population: The FAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Peak Thrombin Generation | 79.5 nmol/L | Standard Deviation 55.3 |
| Eptacog Alfa- Main Part | Peak Thrombin Generation | 98.7 nmol/L | Standard Deviation 20.4 |
| Eptacog Alfa- Main Part | Peak Thrombin Generation | 75.7 nmol/L | Standard Deviation 30.6 |
Secondary
The Number of Bleeding Episodes
The number of bleeding episodes that were treated during at least 76 weeks from treatment onset (week 0) are presented. This outcome measure is applicable for only 'Concizumab' treatment arm.
Time frame: During at least 76 weeks from treatment onset (week 0)
Population: The FAS included all randomised participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concizumab- Main Part | The Number of Bleeding Episodes | 256 episodes |
Secondary
The Number of Spontaneous Bleeding Episodes
Bleeds that were not linked to a specific, known action or event are called spontaneous bleeding episodes. The number of spontaneous bleeding episodes that were treated during at least 76 weeks from treatment onset (week 0) are presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 76 weeks from treatment onset (week 0)
Population: The FAS included all randomised participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concizumab- Main Part | The Number of Spontaneous Bleeding Episodes | 36 episodes |
| Eptacog Alfa- Main Part | The Number of Spontaneous Bleeding Episodes | 9 episodes |
| Eptacog Alfa- Main Part | The Number of Spontaneous Bleeding Episodes | 7 episodes |
Secondary
The Number of Spontaneous Bleeding Episodes
Bleeds that were not linked to a specific, known action or event are called spontaneous bleeding episodes. The number of spontaneous bleeding episodes that were treated during at least 24 weeks from treatment onset (week 0) are presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: During at least 24 weeks from treatment onset (week 0)
Population: The FAS included all randomised participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concizumab- Main Part | The Number of Spontaneous Bleeding Episodes | 19 episodes |
| Eptacog Alfa- Main Part | The Number of Spontaneous Bleeding Episodes | 5 episodes |
| Eptacog Alfa- Main Part | The Number of Spontaneous Bleeding Episodes | 69 episodes |
Secondary
Thrombin Generation Velocity Index
Thrombin generation velocity index prior to the last dose administration at 24 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration at 24 weeks
Population: The FAS included all randomised participants. Overall number of participants analysed = number of participants available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Thrombin Generation Velocity Index | 5.3 nM/min | Standard Deviation 3.3 |
| Eptacog Alfa- Main Part | Thrombin Generation Velocity Index | 14.5 nM/min | Standard Deviation 3.5 |
| Eptacog Alfa- Main Part | Thrombin Generation Velocity Index | 1.0 nM/min | — |
Secondary
Thrombin Generation Velocity Index
Thrombin generation velocity index prior to the last dose administration after at least 76 weeks is presented. The data is presented per the last dose level which the participants have reached at the time of assessment.
Time frame: Prior to the last dose administration after atleast 76 weeks
Population: The FAS included all randomised participants. Overall number of participants analysed = number of participants available for the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concizumab- Main Part | Thrombin Generation Velocity Index | 10.0 nM/min | Standard Deviation 12 |
| Eptacog Alfa- Main Part | Thrombin Generation Velocity Index | 9.7 nM/min | Standard Deviation 3.5 |
| Eptacog Alfa- Main Part | Thrombin Generation Velocity Index | 6.7 nM/min | Standard Deviation 3.2 |