Congenital Bleeding Disorder, Haemophilia B
Conditions
Brief summary
This trial is conducted in Africa, Asia, Europe, Japan and North America. The aim of this trial is to evaluate the safety and efficacy, including pharmacokinetics (the rate at which the body eliminates the trial drug), of NNC-0156-0000-0009 (nonacog beta pegol) when used for treatment and prophylaxis of bleeding episodes in patients with haemophilia B.
Interventions
One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
13 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male patients with moderately severe or severe congenital haemophilia B with a factor IX activity of 2% or below according to medical records * History of at least 150 exposure days to other factor IX products * Patients currently treated on-demand with at least 6 bleeding episodes during the last 12 months or at least 3 bleeding episodes during the last 6 months, or patients currently on prophylaxis
Exclusion criteria
* Known history of factor IX inhibitors based on existing medical records, laboratory report reviews and patient and legally acceptable representative (LAR) interviews * HIV (Human immunodeficiency virus) positive, with a viral load equal to or above 400,000 copies/mL and/or CD4+ lymphocyte count equal to or below 200/microL * Congenital or acquired coagulation disorders other than haemophilia B * Previous arterial thrombotic events (e.g. myocardial infarction and intracranial thrombosis) or previous deep venous thrombosis or pulmonary embolism (as defined by available medical records) * Immune modulating or chemotherapeutic medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units) | 52 weeks after treatment start for patients on prophylaxis | Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of subjects who developed inhibitory antibodies against factor IX are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Haemostatic Effect of NNC-0156-0000-0009 When Used for Treatment of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response | 28 weeks after treatment start on on-demand treatment | Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures. * Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection * Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection * Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours * Poor - no improvement, or worsening of symptoms within 8 hours after two injections. The success rate and 95% confidence interval (CI) are reported here. |
| Number of Bleeding Episodes Per Patient During Routine Prophylaxis | 52 weeks after treatment start for patients on prophylaxis | The number of bleeding episodes per patient during routine prophylaxis was assessed using the individual annualised bleeding rates (spontaneous and traumatic bleeding episodes per patient per year). |
| Factor IX Trough Levels | 52 weeks after treatment start for patients on prophylaxis | The mean pre-dose factor IX levels was measured with the one-stage clotting assay during the trial. Lowest factor IX activity recorded during single-dose and steady state, immediately before next dose was given. The analysis was based on a mixed model on the log-transformed plasma factor IX activity with subject as a random effect. The estimated mean factor IX trough level was presented back-transformed to the natural scale. |
| Haemostatic Effect of NNC-0156-0000-0009 When Used for Prophylaxis of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response | 52 weeks after treatment start for patients on prophylaxis | Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures. * Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection * Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection * Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours * Poor - no improvement, or worsening of symptoms within 8 hours after two injections. The success rate and 95% confidence interval (CI) are reported here. |
| Incidence of Serious Adverse Events (SAEs) | at 56 weeks ±2 weeks for patients on prophylaxis | SAE was defined as an AE that resulted in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. The incidence of SAEs were summarised by the rate of SAEs (number of SAEs per PYE). Number of SAEs per PYE is number of SAEs/total time in trial. All SAEs reported are treatment emergent (any serious adverse events which occurred after trial product administration). |
| Host Cell Proteins (HCP) Antibodies | 52 weeks after treatment start for patients on prophylaxis | Subjects who were positive for anti-Host Cell Protein (HCP) antibodies. |
| Incidence of Adverse Events (AEs) | at 56 weeks ±2 weeks for patients on prophylaxis | The incidence of adverse events were summarised by the rate of AEs (number of AEs per patient years of exposure \[PYE\]). Number of adverse events per PYE is number of adverse events /total time in trial. All adverse events reported are treatment emergent (any adverse events which occurred after trial product administration). |
Countries
Canada, France, Germany, Hungary, Italy, Japan, Malaysia, Netherlands, North Macedonia, Russia, South Africa, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Of the 40 sites that screened subjects, 39 sites enrolled subjects. The trial was therefore conducted at 39 sites in 13 countries, as follows: France (1); Germany (3); Italy (2); Japan (5); Macedonia (2); Malaysia (1) Netherlands (1); Russia (2); South Africa(1); Thailand (2); Turkey (3); United Kingdom (4) and United States (12).
Participants by arm
| Arm | Count |
|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) Subjects were randomised to either prophylaxis 10 U/kg or 40 U/kg arm. Subjects in this arm received 10 U/kg nonacog beta pegol dose once weekly (every 7th day ± 24 hours) for a period of 52 weeks. Nonacog beta pegol was given as an intravenous bolus injection with the maximum injection rate at 4 mL/min. Mild and moderate bleeding episodes were treated with 40 U/kg. Severe bleeding episodes were treated with 80 U/kg. | 30 |
| Prophylaxis, High Dose 40 U/kg (52 Weeks) Subjects were randomised to either prophylaxis 10 U/kg or 40 U/kg arm. Subjects in this arm received 40 U/kg nonacog beta pegol dose once weekly (every 7th day ± 24 hours) for a period of 52 weeks. Nonacog beta pegol was given as an intravenous bolus injection with the maximum injection rate at 4 mL/min. Mild and moderate bleeding episodes were treated with 40 U/kg. Severe bleeding episodes were treated with 80 U/kg. | 29 |
| On-Demand (28 Weeks) Subjects enrolled in this on-demand arm were treated for bleeding episodes on demand with nonacog beta pegol during a period of 28 weeks. Nonacog beta pegol was given as an intravenous bolus injection with the maximum injection rate at 4 mL/min. Mild and moderate bleeding episodes were treated with 40 U/kg. Severe bleeding episodes were treated with 80 U/kg. | 15 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Ineffective therapy | 0 | 0 | 1 |
| Overall Study | Non-compliance | 1 | 0 | 0 |
| Overall Study | patient undergoing major surgery | 0 | 2 | 0 |
| Overall Study | personal reasons | 0 | 0 | 1 |
| Overall Study | unclassified | 1 | 0 | 0 |
| Overall Study | withdrawal criteria | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Prophylaxis, High Dose 40 U/kg (52 Weeks) | On-Demand (28 Weeks) | Total |
|---|---|---|---|---|
| Age, Continuous | 32.4 years STANDARD_DEVIATION 13.9 | 30 years STANDARD_DEVIATION 15.8 | 32.4 years STANDARD_DEVIATION 12 | 31.4 years STANDARD_DEVIATION 14.2 |
| Age, Customized <=17 years | 7 Participants | 9 Participants | 2 Participants | 18 Participants |
| Age, Customized 18-64 years | 23 Participants | 19 Participants | 13 Participants | 55 Participants |
| Age, Customized >=65 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 30 Participants | 29 Participants | 15 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 30 | 19 / 29 | 11 / 15 |
| serious Total, serious adverse events | 1 / 30 | 3 / 29 | 0 / 15 |
Outcome results
Primary
Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units)
Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of subjects who developed inhibitory antibodies against factor IX are reported.
Time frame: 28 weeks after treatment start on on-demand treatment
Population: Full analysis set included all subjects exposed to nonacog beta pegol. Subjects in on-demand arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units) | 0 number of subjects |
Primary
Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units)
Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of subjects who developed inhibitory antibodies against factor IX are reported.
Time frame: 52 weeks after treatment start for patients on prophylaxis
Population: Full analysis set included all subjects exposed to nonacog beta pegol. Subjects in prophylaxis arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units) | 0 Number of subjects |
| Prophylaxis, High Dose 40 U/kg (52 Weeks) | Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units) | 0 Number of subjects |
Secondary
Factor IX Trough Levels
The mean pre-dose factor IX levels was measured with the one-stage clotting assay during the trial. Lowest factor IX activity recorded during single-dose and steady state, immediately before next dose was given. The analysis was based on a mixed model on the log-transformed plasma factor IX activity with subject as a random effect. The estimated mean factor IX trough level was presented back-transformed to the natural scale.
Time frame: 52 weeks after treatment start for patients on prophylaxis
Population: Full analysis set included all subjects exposed to nonacog beta pegol. Subjects in prophylaxis arm were included for this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Factor IX Trough Levels | 0.085 U/mL |
| Prophylaxis, High Dose 40 U/kg (52 Weeks) | Factor IX Trough Levels | 0.273 U/mL |
Secondary
Haemostatic Effect of NNC-0156-0000-0009 When Used for Prophylaxis of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response
Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures. * Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection * Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection * Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours * Poor - no improvement, or worsening of symptoms within 8 hours after two injections. The success rate and 95% confidence interval (CI) are reported here.
Time frame: 52 weeks after treatment start for patients on prophylaxis
Population: Full analysis set included all subjects exposed to nonacog beta pegol. Subjects in prophylaxis arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Haemostatic Effect of NNC-0156-0000-0009 When Used for Prophylaxis of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response | 86.9 percentage of bleeding episodes |
| Prophylaxis, High Dose 40 U/kg (52 Weeks) | Haemostatic Effect of NNC-0156-0000-0009 When Used for Prophylaxis of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response | 97.1 percentage of bleeding episodes |
Secondary
Haemostatic Effect of NNC-0156-0000-0009 When Used for Treatment of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response
Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures. * Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection * Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection * Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours * Poor - no improvement, or worsening of symptoms within 8 hours after two injections. The success rate and 95% confidence interval (CI) are reported here.
Time frame: 28 weeks after treatment start on on-demand treatment
Population: Full analysis set included all subjects exposed to nonacog beta pegol. Subjects in on-demand arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Haemostatic Effect of NNC-0156-0000-0009 When Used for Treatment of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response | 95.1 percentage of bleeding episodes |
Secondary
Host Cell Proteins (HCP) Antibodies
Subjects who were positive for anti-HCP antibodies.
Time frame: 28 weeks after treatment start on on-demand treatment
Population: Safety analysis set included all subjects exposed to nonacog beta pegol. Subjects in on-demand arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Host Cell Proteins (HCP) Antibodies | 0 number of subjects |
Secondary
Host Cell Proteins (HCP) Antibodies
Subjects who were positive for anti-Host Cell Protein (HCP) antibodies.
Time frame: 52 weeks after treatment start for patients on prophylaxis
Population: Safety analysis set included all subjects exposed to nonacog beta pegol. Subjects in prophylaxis arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Host Cell Proteins (HCP) Antibodies | 0 number of subjects |
| Prophylaxis, High Dose 40 U/kg (52 Weeks) | Host Cell Proteins (HCP) Antibodies | 1 number of subjects |
Secondary
Incidence of Adverse Events (AEs)
The incidence of adverse events were summarised by the rate of AEs (number of AEs per PYE). Number of adverse events per PYE is number of adverse events /total time in trial. All adverse events reported are treatment emergent (any adverse events which occurred after trial product administration).
Time frame: at 32 weeks ±2 weeks for patients on on-demand treatment
Population: Safety analysis set included all subjects exposed to nonacog beta pegol.Subjects in on-demand arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Incidence of Adverse Events (AEs) | 4.14 number of AEs per PYE |
Secondary
Incidence of Adverse Events (AEs)
The incidence of adverse events were summarised by the rate of AEs (number of AEs per patient years of exposure \[PYE\]). Number of adverse events per PYE is number of adverse events /total time in trial. All adverse events reported are treatment emergent (any adverse events which occurred after trial product administration).
Time frame: at 56 weeks ±2 weeks for patients on prophylaxis
Population: Safety analysis set included all subjects exposed to nonacog beta pegol. Subjects in prophylaxis arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Incidence of Adverse Events (AEs) | 2.62 number of AEs per PYE |
| Prophylaxis, High Dose 40 U/kg (52 Weeks) | Incidence of Adverse Events (AEs) | 3.83 number of AEs per PYE |
Secondary
Incidence of Serious Adverse Events (SAEs)
SAE was defined as an AE that resulted in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. The incidence of SAEs were summarised by the rate of SAEs (number of SAEs per PYE). Number of SAEs per PYE is number of SAEs/total time in trial. All SAEs reported are treatment emergent (any serious adverse events which occurred after trial product administration).
Time frame: at 56 weeks ±2 weeks for patients on prophylaxis
Population: Safety analysis set included all subjects exposed to nonacog beta pegol. Subjects in prophylaxis arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Incidence of Serious Adverse Events (SAEs) | 0.03 number of SAEs per PYE |
| Prophylaxis, High Dose 40 U/kg (52 Weeks) | Incidence of Serious Adverse Events (SAEs) | 0.11 number of SAEs per PYE |
Secondary
Incidence of Serious Adverse Events (SAEs)
SAE was defined as an AE that resulted in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. The incidence of SAEs were summarised by the rate of SAEs (number of SAEs per PYE). Number of SAEs per PYE is number of SAEs/total time in trial. All SAEs reported are treatment emergent (any serious adverse events which occurred after trial product administration).
Time frame: at 32 weeks ±2 weeks for patients on on-demand treatment
Population: Safety analysis set included all subjects exposed to nonacog beta pegol. Subjects in on-demand arm were included for this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Incidence of Serious Adverse Events (SAEs) | 0 number of SAEs per PYE |
Secondary
Number of Bleeding Episodes Per Patient During Routine Prophylaxis
The number of bleeding episodes per patient during routine prophylaxis was assessed using the individual annualised bleeding rates (spontaneous and traumatic bleeding episodes per patient per year).
Time frame: 52 weeks after treatment start for patients on prophylaxis
Population: Full analysis set included all subjects exposed to nonacog beta pegol. Subjects in prophylaxis arm were included for this analysis.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Prophylaxis, Low Dose 10 U/kg (52 Weeks) | Number of Bleeding Episodes Per Patient During Routine Prophylaxis | 2.93 bleeds/patient/year | Inter-Quartile Range 5.41 |
| Prophylaxis, High Dose 40 U/kg (52 Weeks) | Number of Bleeding Episodes Per Patient During Routine Prophylaxis | 1.04 bleeds/patient/year | Inter-Quartile Range 7.41 |