Congenital Bleeding Disorder, Haemophilia B
Conditions
Brief summary
This trial is conducted globally. The aim of the trial is to investigate the safety and efficacy of nonacog beta pegol (N9-GP) in previously untreated patients with Haemophilia B.
Interventions
For intravenous (i.v.) injection. A single dose of 40 U/kg, unless the bleeding episode is severe in which case it should be treated with 80 U/kg.
Sponsors
Novo Nordisk A/S
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
0 Years to 6 Years
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, age below 6 years at the time of signing informed consent * Patients with the diagnosis of haemophilia B (FIX (coagulation factor IX) activity level below or equal to 2%) based on medical records or central laboratory results * Previously untreated or exposed to FIX containing products less than or equal to 3 exposure days (5 previous exposures to blood components is acceptable)
Exclusion criteria
* Any history of FIX inhibitors (defined by medical records) * Known or suspected hypersensitivity to trial product or related products * Previous participation in this trial. Participation is defined as first dose administered of trial product * Receipt of any investigational medicinal product within 30 days before screening * Congenital or acquired coagulation disorder other than haemophilia B * Any chronic disorder or severe disease which, in the opinion of the Investigator, might jeopardise the patient's safety or compliance with the protocol * Patient's parent(s)/LAR(s) (legally acceptable representative) mental incapacity, unwillingness to cooperate, or a language barrier precluding adequate understanding and cooperation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) (50 Exposure Days) | When minimum 20 previously untreated patients (PUPs) have reached at least 50 exposure days (ED) (up to 156 weeks) | Number of participants with incidence of inihibitory antibodies against FIX after 50 ED is presented and defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies. |
| Number of Participants With Incidence of Inhibitory Antibodies Against FIX (100 ED) | When minimum 40 PUPs have reached at least 100 ED (up to 208 weeks) | Number of participants with incidence of inihibitory antibodies against FIX after 100 ED is presented and defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies. |
| Number of Participants With Incidence of Inhibitory Antibodies Against FIX (At End of Trial) | At end of trial (up to 434 weeks) | Number of participants with incidence of inihibitory antibodies against FIX at end of trial is presented and defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Serious Adverse Events | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | Frequency of serious adverse events after 50 ED, after 100 ED, and at end of trial is presented. Frequency of serious adverse events was expressed as number of serious adverse events per participant years of exposure (total number of events /total time in trial). A serious adverse event was an experience that at any dose resulted in: death; life-threatening experience; in-patient hospitalisation or prolongation of existing hospitalisation; a persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events that may not result in death, be life-threatening/require hospitalisation could be considered a serious adverse event based upon appropriate medical judgement. |
| Number of Medical Events of Special Interest | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | Number of medical events of special interest after 50 ED, after 100 ED, and at end of trial is presented. A medical event of special interest (MESI) was an event that, in the evaluation of safety, has a special focus. A MESI was an adverse event (serious or non-serious adverse event) that fulfils one or more of the following MESI criteria: 1. Medication errors concerning the trial product; 2. Inhibitor formation against FIX; 3. Thromboembolic events; 4. Anaphylactic reaction; 5. Allergic reaction including, but not limited to, any acute immunoglobulin E mediated reaction of delayed-type hypersensitivity (clinical signs may include various types of skin rashes) that does not meet the definition of anaphylaxis; 6. CNS-related adverse events including, but not limited to, any learning and behavioral deficits; 7. Renal adverse events including new onset of renal disorder or renal impairment or acute and chronic renal failure. |
| Frequency of Medical Events of Special Interest | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | Frequency of medical events of special interest after 50 ED, after 100 ED, and at end of trial is presented. It was expressed as number of MESI per participant years of exposure (total number of events/total time in trial). A MESI was an event that, in the evaluation of safety, has a special focus. A MESI was an adverse event that fulfils one or more of the MESI criteria: 1. Medication errors concerning the trial product; 2. Inhibitor formation against FIX; 3. Thromboembolic events; 4. Anaphylactic reaction; 5. Allergic reaction including, but not limited to, any acute immunoglobulin E mediated reaction of delayed-type hypersensitivity (clinical signs may include various types of skin rashes) that does not meet the definition of anaphylaxis; 6. CNS-related adverse events including, but not limited to, any learning and behavioral deficits; 7. Renal adverse events including new onset of renal disorder or renal impairment or acute and chronic renal failure. |
| Number of Breakthrough Bleeding Episodes During Prophylaxis (Annualised Bleeding Rate) | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | Number of breakthrough bleeding episodes during prophylaxis (annualised bleeding rate) after 50 ED, after 100 ED, and at end of trial is presented. Annualised bleeding rate is the number of bleeding episodes per year. |
| Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | Haemostatic effect of nonacog beta pegol in treatment of bleeding episodes by 4-point haemostatic response scale after 50 ED, after 100 ED, and at end of trial is presented. The haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4-point scale as excellent, good, moderate or poor. Excellent: abrupt pain relief and/or clear improvement in objective signs of bleeding; Good: noticeable pain relief and/or improvement in signs of bleeding; Moderate: probable or slight beneficial effect after the first injection; Poor: no improvement or worsening of symptoms. If the haemostatic response was rated as excellent or good, the treatment of the bleed was considered a success. If the haemostatic response was rated as moderate or poor, the treatment was considered a failure. |
| Number of Adverse Events | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | Number of adverse events after 50 ED, after 100 ED, and at end of trial is presented. An adverse event was defined as any untoward medical occurrence in a participant who was administered a product, and which does not necessarily have a causal relationship with this treatment. All presented adverse events are treatment emergent adverse events, defined as an event that occured while the participant was on treatment in the period from first dosing with nonacog beta pegol to the end of trial/discontinuation of treatment. |
| FIX Activity at 30 Minutes (C30min) | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks) | FIX Activity 30 minutes post dosing (C30min) after 50 ED, after 100 ED is presented. The FIX activity was measured by one-stage clotting assay - a modified activated partial thromboplastin time (aPTT) assay. |
| FIX Trough Levels | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | FIX trough levels after 50 ED, after 100 ED, and at end of trial is presented. FIX trough level was defined as the activity recorded immediately before nonacog beta pegol injection was given and was measured by one-stage clotting assay - a modified activated partial thromboplastin time (aPTT) assay. The analysis is based on a mixed model on the log-transformed plasma concentrations with participant as a random effect. The mean trough level is presented back-transformed to the natural scale. |
| Amount of Drug Administered to Treat a Bleeding Episode | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | Amount of nonacog beta pegol administered (average dose of nonacog beta pegol) to treat a bleeding episode after 50 ED, after 100 ED, and at end of trial is presented as international units per kilogram per bleed (IU/kg/bleed). |
| Number of Injections Needed to Treat a Bleeding Episode | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | The mean number of injections needed to treat a bleeding episode is presented. |
| Incremental Recovery at 30 Minutes (IR30min) | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks) | Incremental recovery 30 minutes post dosing (IR30min) after 50 ED, after 100 ED is presented. IR30min was defined as the rise in FIX activity per international units per kilogram (IU/kg) administered and was recorded 30 minutes after the end of nonacog beta pegol injection. It was calculated as the baseline adjusted FIX activity recorded 30 minutes after ended nonacog beta pegol injection divided by the administered dose (IU/kg body weight). It was recorded as international units per milliliter (IU/mL)/international units per kilogram (IU/kg). |
| Frequency of Adverse Events | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | Frequency of adverse events after 50 ED, after 100 ED, and at end of trial is presented. Frequency of adverse events was expressed as number of adverse events per participant years of exposure (total number of events /total time in trial). An adverse event was defined as any untoward medical occurrence in a participant who was administered a product, and which does not necessarily have a causal relationship with this treatment. All presented adverse events are treatment emergent adverse events, defined as an event that occured while the participant was on treatment in the period from first dosing with nonacog beta pegol to the end of trial/discontinuation of treatment. |
| Number of Serious Adverse Events | When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks) | Number of serious adverse events after 50 ED, after 100 ED, and at end of trial is presented. A serious adverse event was an experience that at any dose resulted in: death; life-threatening experience; in-patient hospitalisation or prolongation of existing hospitalisation; a persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events that may not result in death, be life-threatening/require hospitalisation could be considered a serious adverse event based upon appropriate medical judgement. |
Countries
Algeria, Argentina, Australia, Austria, Bulgaria, Canada, France, Germany, Greece, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Portugal, Romania, Serbia, Spain, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 29 sites in 11 countries as follows (number of sites that screened participants/ number of sites that randomised participants): Australia (1/1); Austria (2/2); Canada (1/1); Israel (1/1); Japan (1/1); Malaysia (4/4); Spain (3/3); Taiwan (2/2); Thailand (2/2); United Kingdom (3/3); United States (9/9).
Pre-assignment details
Trial consists of main phase including pre-prophylaxis & prophylaxis, extension phase & prophylaxis period until end of treatment. Pre-prophylaxis was optional and allowed participants to receive treatment until 24 months of age/upon reaching 20EDs, whichever came first. Other participants directly started on prophylaxis treatment at visit 1.
Participants by arm
| Arm | Count |
|---|---|
| Nonacog Beta Pegol Participants received pre-prophylaxis treatment of nonacog beta pegol 40 IU/kg intravenous injection at intervals longer than a week on-demand for bleeding episodes until they were 24 months of age or until 20 exposure days (ED) whichever came first in the main phase. After which they switched to prophylaxis treatment. In prophylaxis, participants received nonacog beta pegol 40 IU/kg intravenous injection once weekly in the main phase, extension phase and until end of treatment. | 54 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Pre-prophylaxis | Adverse Event | 3 | 0 |
| Prophylaxis | Adverse Event | 0 | 4 |
| Prophylaxis | Withdrawal by parent/guardian | 0 | 2 |
| Prophylaxis | Withdrawal by Subject | 0 | 1 |
| Prophylaxis | Withdrawn due to closure of trial | 0 | 3 |
Baseline characteristics
| Characteristic | Nonacog Beta Pegol |
|---|---|
| Age, Continuous | 0.8 years STANDARD_DEVIATION 1.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 19 Participants |
| Race/Ethnicity, Customized Black or African American | 7 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Race/Ethnicity, Customized White | 25 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 34 | 1 / 51 |
| other Total, other adverse events | 22 / 34 | 46 / 51 |
| serious Total, serious adverse events | 9 / 34 | 19 / 51 |
Outcome results
Primary
Number of Participants With Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) (50 Exposure Days)
Number of participants with incidence of inihibitory antibodies against FIX after 50 ED is presented and defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies.
Time frame: When minimum 20 previously untreated patients (PUPs) have reached at least 50 exposure days (ED) (up to 156 weeks)
Population: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pre-prophylaxis | Number of Participants With Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) (50 Exposure Days) | 2 Participants |
| Prophylaxis | Number of Participants With Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) (50 Exposure Days) | 0 Participants |
Primary
Number of Participants With Incidence of Inhibitory Antibodies Against FIX (100 ED)
Number of participants with incidence of inihibitory antibodies against FIX after 100 ED is presented and defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies.
Time frame: When minimum 40 PUPs have reached at least 100 ED (up to 208 weeks)
Population: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pre-prophylaxis | Number of Participants With Incidence of Inhibitory Antibodies Against FIX (100 ED) | 2 Participants |
| Prophylaxis | Number of Participants With Incidence of Inhibitory Antibodies Against FIX (100 ED) | 2 Participants |
Primary
Number of Participants With Incidence of Inhibitory Antibodies Against FIX (At End of Trial)
Number of participants with incidence of inihibitory antibodies against FIX at end of trial is presented and defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies.
Time frame: At end of trial (up to 434 weeks)
Population: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pre-prophylaxis | Number of Participants With Incidence of Inhibitory Antibodies Against FIX (At End of Trial) | 2 Participants |
| Prophylaxis | Number of Participants With Incidence of Inhibitory Antibodies Against FIX (At End of Trial) | 2 Participants |
Secondary
Amount of Drug Administered to Treat a Bleeding Episode
Amount of nonacog beta pegol administered (average dose of nonacog beta pegol) to treat a bleeding episode after 50 ED, after 100 ED, and at end of trial is presented as international units per kilogram per bleed (IU/kg/bleed).
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Full analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre-prophylaxis | Amount of Drug Administered to Treat a Bleeding Episode | 50 ED | 55.0 IU/kg/bleed | Standard Deviation 28.7 |
| Pre-prophylaxis | Amount of Drug Administered to Treat a Bleeding Episode | 100 ED | 47.7 IU/kg/bleed | Standard Deviation 17.6 |
| Pre-prophylaxis | Amount of Drug Administered to Treat a Bleeding Episode | End of trial (Week 434) | 47.5 IU/kg/bleed | Standard Deviation 17.4 |
| Prophylaxis | Amount of Drug Administered to Treat a Bleeding Episode | 50 ED | 48.8 IU/kg/bleed | Standard Deviation 16.9 |
| Prophylaxis | Amount of Drug Administered to Treat a Bleeding Episode | 100 ED | 58.5 IU/kg/bleed | Standard Deviation 70 |
| Prophylaxis | Amount of Drug Administered to Treat a Bleeding Episode | End of trial (Week 434) | 54.0 IU/kg/bleed | Standard Deviation 53.5 |
Secondary
FIX Activity at 30 Minutes (C30min)
FIX Activity 30 minutes post dosing (C30min) after 50 ED, after 100 ED is presented. The FIX activity was measured by one-stage clotting assay - a modified activated partial thromboplastin time (aPTT) assay.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks)
Population: Full analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pre-prophylaxis | FIX Activity at 30 Minutes (C30min) | 50 ED | 0.652 IU/mL | Geometric Coefficient of Variation 39.5 |
| Pre-prophylaxis | FIX Activity at 30 Minutes (C30min) | 100 ED | 0.824 IU/mL | Geometric Coefficient of Variation 21.6 |
Secondary
FIX Trough Levels
FIX trough levels after 50 ED, after 100 ED, and at end of trial is presented. FIX trough level was defined as the activity recorded immediately before nonacog beta pegol injection was given and was measured by one-stage clotting assay - a modified activated partial thromboplastin time (aPTT) assay. The analysis is based on a mixed model on the log-transformed plasma concentrations with participant as a random effect. The mean trough level is presented back-transformed to the natural scale.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Full analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Pre-prophylaxis | FIX Trough Levels | 50 ED | 0.150 IU/mL |
| Pre-prophylaxis | FIX Trough Levels | 100 ED | 0.156 IU/mL |
| Pre-prophylaxis | FIX Trough Levels | End of trial (Week 434) | 0.167 IU/mL |
Secondary
Frequency of Adverse Events
Frequency of adverse events after 50 ED, after 100 ED, and at end of trial is presented. Frequency of adverse events was expressed as number of adverse events per participant years of exposure (total number of events /total time in trial). An adverse event was defined as any untoward medical occurrence in a participant who was administered a product, and which does not necessarily have a causal relationship with this treatment. All presented adverse events are treatment emergent adverse events, defined as an event that occured while the participant was on treatment in the period from first dosing with nonacog beta pegol to the end of trial/discontinuation of treatment.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pre-prophylaxis | Frequency of Adverse Events | 50 ED | 5.59 Events per participant years of exposure |
| Pre-prophylaxis | Frequency of Adverse Events | 100 ED | 5.92 Events per participant years of exposure |
| Pre-prophylaxis | Frequency of Adverse Events | End of trial (Week 434) | 5.52 Events per participant years of exposure |
| Prophylaxis | Frequency of Adverse Events | 50 ED | 5.87 Events per participant years of exposure |
| Prophylaxis | Frequency of Adverse Events | 100 ED | 5.08 Events per participant years of exposure |
| Prophylaxis | Frequency of Adverse Events | End of trial (Week 434) | 4.10 Events per participant years of exposure |
Secondary
Frequency of Medical Events of Special Interest
Frequency of medical events of special interest after 50 ED, after 100 ED, and at end of trial is presented. It was expressed as number of MESI per participant years of exposure (total number of events/total time in trial). A MESI was an event that, in the evaluation of safety, has a special focus. A MESI was an adverse event that fulfils one or more of the MESI criteria: 1. Medication errors concerning the trial product; 2. Inhibitor formation against FIX; 3. Thromboembolic events; 4. Anaphylactic reaction; 5. Allergic reaction including, but not limited to, any acute immunoglobulin E mediated reaction of delayed-type hypersensitivity (clinical signs may include various types of skin rashes) that does not meet the definition of anaphylaxis; 6. CNS-related adverse events including, but not limited to, any learning and behavioral deficits; 7. Renal adverse events including new onset of renal disorder or renal impairment or acute and chronic renal failure.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pre-prophylaxis | Frequency of Medical Events of Special Interest | 100 ED | 0.27 Events per participant years of exposure |
| Pre-prophylaxis | Frequency of Medical Events of Special Interest | End of trial (Week 434) | 0.25 Events per participant years of exposure |
| Pre-prophylaxis | Frequency of Medical Events of Special Interest | 50 ED | 0.33 Events per participant years of exposure |
| Prophylaxis | Frequency of Medical Events of Special Interest | End of trial (Week 434) | 0.20 Events per participant years of exposure |
| Prophylaxis | Frequency of Medical Events of Special Interest | 50 ED | 0.18 Events per participant years of exposure |
| Prophylaxis | Frequency of Medical Events of Special Interest | 100 ED | 0.26 Events per participant years of exposure |
Secondary
Frequency of Serious Adverse Events
Frequency of serious adverse events after 50 ED, after 100 ED, and at end of trial is presented. Frequency of serious adverse events was expressed as number of serious adverse events per participant years of exposure (total number of events /total time in trial). A serious adverse event was an experience that at any dose resulted in: death; life-threatening experience; in-patient hospitalisation or prolongation of existing hospitalisation; a persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events that may not result in death, be life-threatening/require hospitalisation could be considered a serious adverse event based upon appropriate medical judgement.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pre-prophylaxis | Frequency of Serious Adverse Events | 50 ED | 0.59 Events per participant years of exposure |
| Pre-prophylaxis | Frequency of Serious Adverse Events | 100 ED | 0.59 Events per participant years of exposure |
| Pre-prophylaxis | Frequency of Serious Adverse Events | End of trial (Week 434) | 0.58 Events per participant years of exposure |
| Prophylaxis | Frequency of Serious Adverse Events | 50 ED | 0.28 Events per participant years of exposure |
| Prophylaxis | Frequency of Serious Adverse Events | 100 ED | 0.22 Events per participant years of exposure |
| Prophylaxis | Frequency of Serious Adverse Events | End of trial (Week 434) | 0.15 Events per participant years of exposure |
Secondary
Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor)
Haemostatic effect of nonacog beta pegol in treatment of bleeding episodes by 4-point haemostatic response scale after 50 ED, after 100 ED, and at end of trial is presented. The haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4-point scale as excellent, good, moderate or poor. Excellent: abrupt pain relief and/or clear improvement in objective signs of bleeding; Good: noticeable pain relief and/or improvement in signs of bleeding; Moderate: probable or slight beneficial effect after the first injection; Poor: no improvement or worsening of symptoms. If the haemostatic response was rated as excellent or good, the treatment of the bleed was considered a success. If the haemostatic response was rated as moderate or poor, the treatment was considered a failure.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Full analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 100 ED Excellent | 44 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 50 ED Excellent | 23 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 50 ED Good | 8 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 50 ED Moderate | 2 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 50 ED Poor | 0 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 100 ED Good | 17 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 100 ED Moderate | 2 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 100 ED Poor | 0 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | End of trial (Week 434) Excellent | 45 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | End of trial (Week 434) Good | 18 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | End of trial (Week 434) Moderate | 2 Number of bleeds treated |
| Pre-prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | End of trial (Week 434) Poor | 0 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | End of trial (Week 434) Moderate | 4 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 100 ED Excellent | 44 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 100 ED Moderate | 3 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 50 ED Excellent | 9 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | End of trial (Week 434) Good | 45 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 50 ED Good | 5 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 100 ED Poor | 0 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 50 ED Moderate | 1 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | End of trial (Week 434) Poor | 0 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 50 ED Poor | 0 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | End of trial (Week 434) Excellent | 86 Number of bleeds treated |
| Prophylaxis | Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale (Excellent, Good, Moderate and Poor) | 100 ED Good | 30 Number of bleeds treated |
Secondary
Incremental Recovery at 30 Minutes (IR30min)
Incremental recovery 30 minutes post dosing (IR30min) after 50 ED, after 100 ED is presented. IR30min was defined as the rise in FIX activity per international units per kilogram (IU/kg) administered and was recorded 30 minutes after the end of nonacog beta pegol injection. It was calculated as the baseline adjusted FIX activity recorded 30 minutes after ended nonacog beta pegol injection divided by the administered dose (IU/kg body weight). It was recorded as international units per milliliter (IU/mL)/international units per kilogram (IU/kg).
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks)
Population: Full analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pre-prophylaxis | Incremental Recovery at 30 Minutes (IR30min) | 50 ED | 0.012 (IU/mL)/(IU/kg) | Geometric Coefficient of Variation 13.9 |
| Pre-prophylaxis | Incremental Recovery at 30 Minutes (IR30min) | 100 ED | 0.014 (IU/mL)/(IU/kg) | Geometric Coefficient of Variation 20.1 |
Secondary
Number of Adverse Events
Number of adverse events after 50 ED, after 100 ED, and at end of trial is presented. An adverse event was defined as any untoward medical occurrence in a participant who was administered a product, and which does not necessarily have a causal relationship with this treatment. All presented adverse events are treatment emergent adverse events, defined as an event that occured while the participant was on treatment in the period from first dosing with nonacog beta pegol to the end of trial/discontinuation of treatment.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pre-prophylaxis | Number of Adverse Events | 50 ED | 86 Events |
| Pre-prophylaxis | Number of Adverse Events | 100 ED | 131 Events |
| Pre-prophylaxis | Number of Adverse Events | End of trial (Week 434) | 134 Events |
| Prophylaxis | Number of Adverse Events | 100 ED | 610 Events |
| Prophylaxis | Number of Adverse Events | 50 ED | 291 Events |
| Prophylaxis | Number of Adverse Events | End of trial (Week 434) | 794 Events |
Secondary
Number of Breakthrough Bleeding Episodes During Prophylaxis (Annualised Bleeding Rate)
Number of breakthrough bleeding episodes during prophylaxis (annualised bleeding rate) after 50 ED, after 100 ED, and at end of trial is presented. Annualised bleeding rate is the number of bleeding episodes per year.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Full analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pre-prophylaxis | Number of Breakthrough Bleeding Episodes During Prophylaxis (Annualised Bleeding Rate) | 50 ED | 0.00 bleeds/participant/year |
| Pre-prophylaxis | Number of Breakthrough Bleeding Episodes During Prophylaxis (Annualised Bleeding Rate) | 100 ED | 0.25 bleeds/participant/year |
| Pre-prophylaxis | Number of Breakthrough Bleeding Episodes During Prophylaxis (Annualised Bleeding Rate) | End of trial (Week 434) | 0.33 bleeds/participant/year |
Secondary
Number of Injections Needed to Treat a Bleeding Episode
The mean number of injections needed to treat a bleeding episode is presented.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Full analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre-prophylaxis | Number of Injections Needed to Treat a Bleeding Episode | 50 ED | 1.3 Injections per bleed | Standard Deviation 0.7 |
| Pre-prophylaxis | Number of Injections Needed to Treat a Bleeding Episode | 100 ED | 1.1 Injections per bleed | Standard Deviation 0.4 |
| Pre-prophylaxis | Number of Injections Needed to Treat a Bleeding Episode | End of trial (Week 434) | 1.1 Injections per bleed | Standard Deviation 0.4 |
| Prophylaxis | Number of Injections Needed to Treat a Bleeding Episode | 100 ED | 1.3 Injections per bleed | Standard Deviation 1.5 |
| Prophylaxis | Number of Injections Needed to Treat a Bleeding Episode | 50 ED | 1.0 Injections per bleed | Standard Deviation 0 |
| Prophylaxis | Number of Injections Needed to Treat a Bleeding Episode | End of trial (Week 434) | 1.2 Injections per bleed | Standard Deviation 1.2 |
Secondary
Number of Medical Events of Special Interest
Number of medical events of special interest after 50 ED, after 100 ED, and at end of trial is presented. A medical event of special interest (MESI) was an event that, in the evaluation of safety, has a special focus. A MESI was an adverse event (serious or non-serious adverse event) that fulfils one or more of the following MESI criteria: 1. Medication errors concerning the trial product; 2. Inhibitor formation against FIX; 3. Thromboembolic events; 4. Anaphylactic reaction; 5. Allergic reaction including, but not limited to, any acute immunoglobulin E mediated reaction of delayed-type hypersensitivity (clinical signs may include various types of skin rashes) that does not meet the definition of anaphylaxis; 6. CNS-related adverse events including, but not limited to, any learning and behavioral deficits; 7. Renal adverse events including new onset of renal disorder or renal impairment or acute and chronic renal failure.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pre-prophylaxis | Number of Medical Events of Special Interest | 50 ED | 5 Events |
| Pre-prophylaxis | Number of Medical Events of Special Interest | 100 ED | 6 Events |
| Pre-prophylaxis | Number of Medical Events of Special Interest | End of trial (Week 434) | 6 Events |
| Prophylaxis | Number of Medical Events of Special Interest | 50 ED | 9 Events |
| Prophylaxis | Number of Medical Events of Special Interest | 100 ED | 31 Events |
| Prophylaxis | Number of Medical Events of Special Interest | End of trial (Week 434) | 38 Events |
Secondary
Number of Serious Adverse Events
Number of serious adverse events after 50 ED, after 100 ED, and at end of trial is presented. A serious adverse event was an experience that at any dose resulted in: death; life-threatening experience; in-patient hospitalisation or prolongation of existing hospitalisation; a persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events that may not result in death, be life-threatening/require hospitalisation could be considered a serious adverse event based upon appropriate medical judgement.
Time frame: When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Population: Safety analysis set included all participants exposed to nonacog beta pegol. Overall Number of Participants Analyzed = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pre-prophylaxis | Number of Serious Adverse Events | 100 ED | 13 Events |
| Pre-prophylaxis | Number of Serious Adverse Events | 50 ED | 9 Events |
| Pre-prophylaxis | Number of Serious Adverse Events | End of trial (Week 434) | 14 Events |
| Prophylaxis | Number of Serious Adverse Events | 50 ED | 14 Events |
| Prophylaxis | Number of Serious Adverse Events | 100 ED | 27 Events |
| Prophylaxis | Number of Serious Adverse Events | End of trial (Week 434) | 30 Events |