Congenital Bleeding Disorder, Haemophilia A
Conditions
Brief summary
This trial is conducted globally. The aim of the trial is to investigate safety, efficacy and pharmacokinetics (the exposure of the trial drug in the body) of NNC 0129-0000-1003 (N8-GP) in children with severe haemophilia A who have undergone treatment with previous factor VIII (FVIII) products.
Interventions
Fixed dose of turoctocog alfa pegol for intravenous injections (i.v.) twice weekly for prophylaxis. In addition, turoctocog alfa pegol will be administered to treat bleeding episodes during the trial period. Bleeding episodes will be treated with doses of 20-75 U/kg body weight.
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 11 Years
Healthy volunteers
No
Inclusion criteria
* Male patients with severe congenital haemophilia A (FVIII activity level below 1%) * Weight above or equal to 10 kg - Documented history of 150 exposure days (ED) to FVIII products for patients aged 6-11 years and above 50 ED to FVIII products for patients aged 0-5 years
Exclusion criteria
\- Any history of FVIII inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Inhibitory Antibodies Against Coagulation Factor VIII (FVIII) ≥0.6 Bethesda Units | During the main phase of the trial (from 0-26 weeks of treatment) | The number of participants with inhibitory antibodies against coagulation factor VIII (FVIII) ≥0.6 Bethesda units was presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years) | Haemostatic effect of N8-GP for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Evaluation during trial was done by patient and/or parent(s)/caregiver 8 hours after first injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hours after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but possibly requiring more than one injection for complete resolution; Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection, but usually requiring more than one injection; None: No improvement, or worsening of symptoms. |
| Number of Bleeding Episodes During Prophylactic Treatment With N8-GP (Annualised Bleeding Rate) | Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years) | The number of bleeding episodes per year reported during the prophylactic treatment with N8-GP. |
| Consumption of N8-GP Per Bleeding Episode (Number of Injections) | Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years) | The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed. |
| Consumption of N8-GP Per Bleeding Episode (U/kg) | Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years) | The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed. |
| Consumption of N8-GP During Prophylaxis (Number of Injections) | Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years) | The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis. |
| Consumption of N8-GP During Prophylaxis (U/kg Per Month) | Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years) | The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis (per month per subject). Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics \[PK\]) |
| Consumption of N8-GP During Prophylaxis (U/kg Per Year) | Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years) | The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis (per year per subject). Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics) |
| Frequency of Adverse Events Including Serious Adverse Events Reported During the Trial Period | Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years) | The frequency of adverse events including serious adverse events reported during the main and extension phase of the trial. The data presented is the rate of AE i.e. number of AEs per patient years of exposue. |
| Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for N8-GP | From 1 hour prior to and up to 96 hours after initial administration of N8-GP | The incremental recovery was defined as the peak level recorded 60 min after end of injection and dose-normalised. It was calculated as (FVIII:C activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with product specific calibrator (PSS) as calibrator was used. |
| Area Under the Curve Evaluated for Previous FVIII Product | 2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product | Area under the curve (AUC) versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with NHP as calibrator was used. |
| Area Under the Curve Evaluated for N8-GP | From 1 hour prior to and up to 96 hours after initial administration of N8-GP | Area under the curve versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with product specific standard (PSS) as calibrator was used. |
| Terminal Half-life Evaluated for Previous FVIII Product | 2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product | t½ = ln(2) / λz, where t½ is terminal half-life and λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the lower limit of quantification (LLOQ). This was estimated using time points from 1h to 30h. A chromogenic assay with PSS as calibrator was used. |
| Terminal Half-life Evaluated for N8-GP | From 1 hour prior to and up to 96 hours after initial administration of N8-GP | t½ = ln(2) / λz, where λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the LLOQ. This was estimated using time points from 6h to 96h. A chromogenic assay with PSS as calibrator was used. |
| Clearance Evaluated for Previous FVIII Product | 2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product | Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with NHP as calibrator was used. |
| Clearance Evaluated for N8-GP | From 1 hour prior to and up to 96 hours after initial administration of N8-GP. | Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with PSS as calibrator was used. |
| Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for Previous FVIII Product | 2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product | The incremental recovery was defined as the increase in plasma FVIII activity per IU/kg of factor administered recorded 60 minutes after end of injection. It was calculated as (Factor VIII procoagulant \[FVIII:C\] activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with normal human plasma (NHP) as calibrator was used. |
Countries
Brazil, Canada, France, Greece, Israel, Italy, Japan, Lithuania, Malaysia, Portugal, Puerto Rico, Switzerland, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 36 sites in 15 countries as follows: Canada (1), France (2), Germany (1), Greece (2 sites screened/1 site randomised subjects), Israel (1), Italy (1), Japan (2), Lithuania (1), Malaysia (1), Portugal (1), Switzerland (3), Turkey (3), Ukraine (2), United Kingdom (3), and United States (12).
Participants by arm
| Arm | Count |
|---|---|
| Younger Children (0 - 5 Years) Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). Prophylaxis: N8-GP as a single bolus iv injection 60 IU/kg twice weekly. Treatment of bleeding episodes: N8-GP ranging from 20-75 IU/kg, according to severity and location of bleeding episode. The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities. | 34 |
| Older Children (6 - 11 Years) Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). Prophylaxis: N8-GP as a single bolus iv injection 60 IU/kg twice weekly. Treatment of bleeding episodes: N8-GP ranging from 20-75 IU/kg, according to severity and location of bleeding episode. The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities. | 34 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Other reasons | 3 | 0 |
| Overall Study | Withdrawal criteria | 1 | 0 |
Baseline characteristics
| Characteristic | Younger Children (0 - 5 Years) | Older Children (6 - 11 Years) | Total |
|---|---|---|---|
| Age, Continuous | 3.0 years STANDARD_DEVIATION 1.3 | 8.9 years STANDARD_DEVIATION 1.7 | 6.0 years STANDARD_DEVIATION 3.3 |
| Age, Customized Children (2-11 years) | 28 Participants | 34 Participants | 62 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 6 Participants | 0 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 30 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Not applicable | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 30 Participants | 25 Participants | 55 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 34 Participants | 34 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 34 |
| other Total, other adverse events | 33 / 34 | 33 / 34 |
| serious Total, serious adverse events | 11 / 34 | 5 / 34 |
Outcome results
Primary
Number of Participants With Inhibitory Antibodies Against Coagulation Factor VIII (FVIII) ≥0.6 Bethesda Units
The number of participants with inhibitory antibodies against coagulation factor VIII (FVIII) ≥0.6 Bethesda units was presented.
Time frame: During the main phase of the trial (from 0-26 weeks of treatment)
Population: Results were based on safety analysis set (SAS). The SAS consists of all patients exposed to at least one dose of turoctocog alfa pegol. Number analysed = participants with minimum of 50 exposure days and developed inhibitory antibodies
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Number of Participants With Inhibitory Antibodies Against Coagulation Factor VIII (FVIII) ≥0.6 Bethesda Units | 0 Participants |
| Older Children (6 - 11 Years) [Main Trial] | Number of Participants With Inhibitory Antibodies Against Coagulation Factor VIII (FVIII) ≥0.6 Bethesda Units | 0 Participants |
Comparison: A one-sided, upper 97.5% confidence limit was provided based on an exact calculation in the binomial distribution.
Secondary
Area Under the Curve Evaluated for N8-GP
Area under the curve versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with product specific standard (PSS) as calibrator was used.
Time frame: From 1 hour prior to and up to 96 hours after initial administration of N8-GP
Population: Results were based on FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Area Under the Curve Evaluated for N8-GP | 21.489 IU*h/mL |
| Older Children (6 - 11 Years) [Main Trial] | Area Under the Curve Evaluated for N8-GP | 25.026 IU*h/mL |
Secondary
Area Under the Curve Evaluated for Previous FVIII Product
Area under the curve (AUC) versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with NHP as calibrator was used.
Time frame: 2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product
Population: Results were based on FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Area Under the Curve Evaluated for Previous FVIII Product | 11.628 IU×h/mL |
| Older Children (6 - 11 Years) [Main Trial] | Area Under the Curve Evaluated for Previous FVIII Product | 12.203 IU×h/mL |
Secondary
Clearance Evaluated for N8-GP
Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with PSS as calibrator was used.
Time frame: From 1 hour prior to and up to 96 hours after initial administration of N8-GP.
Population: Results were based on FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Clearance Evaluated for N8-GP | 2.601 mL/h/kg |
| Older Children (6 - 11 Years) [Main Trial] | Clearance Evaluated for N8-GP | 2.386 mL/h/kg |
Secondary
Clearance Evaluated for Previous FVIII Product
Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with NHP as calibrator was used.
Time frame: 2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product
Population: Results were based on FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Clearance Evaluated for Previous FVIII Product | 4.322 mL/h/kg |
| Older Children (6 - 11 Years) [Main Trial] | Clearance Evaluated for Previous FVIII Product | 3.867 mL/h/kg |
Secondary
Consumption of N8-GP During Prophylaxis (Number of Injections)
The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis.
Time frame: Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)
Population: Results were based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Consumption of N8-GP During Prophylaxis (Number of Injections) | 65.3 Number of injections | Standard Deviation 6.5 |
| Older Children (6 - 11 Years) [Main Trial] | Consumption of N8-GP During Prophylaxis (Number of Injections) | 62.3 Number of injections | Standard Deviation 7.4 |
| Younger Children (0 - 5 Years) [Full Trial] | Consumption of N8-GP During Prophylaxis (Number of Injections) | 65.4 Number of injections | Standard Deviation 7.5 |
| Older Children (6 - 11 Years) [Full Trial] | Consumption of N8-GP During Prophylaxis (Number of Injections) | 64.1 Number of injections | Standard Deviation 5.3 |
Secondary
Consumption of N8-GP During Prophylaxis (U/kg Per Month)
The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis (per month per subject). Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics \[PK\])
Time frame: Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)
Population: Results were based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Consumption of N8-GP During Prophylaxis (U/kg Per Month) | 572.5 U/kg/month | Standard Deviation 97.4 |
| Older Children (6 - 11 Years) [Main Trial] | Consumption of N8-GP During Prophylaxis (U/kg Per Month) | 555.8 U/kg/month | Standard Deviation 44.6 |
| Younger Children (0 - 5 Years) [Full Trial] | Consumption of N8-GP During Prophylaxis (U/kg Per Month) | 564.9 U/kg/month | Standard Deviation 86.6 |
| Older Children (6 - 11 Years) [Full Trial] | Consumption of N8-GP During Prophylaxis (U/kg Per Month) | 563.4 U/kg/month | Standard Deviation 15.1 |
Secondary
Consumption of N8-GP During Prophylaxis (U/kg Per Year)
The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis (per year per subject). Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics)
Time frame: Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)
Population: Results were based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Consumption of N8-GP During Prophylaxis (U/kg Per Year) | 6870.3 U/kg/year | Standard Deviation 1169 |
| Older Children (6 - 11 Years) [Main Trial] | Consumption of N8-GP During Prophylaxis (U/kg Per Year) | 6669.6 U/kg/year | Standard Deviation 535.8 |
| Younger Children (0 - 5 Years) [Full Trial] | Consumption of N8-GP During Prophylaxis (U/kg Per Year) | 6778.6 U/kg/year | Standard Deviation 1039 |
| Older Children (6 - 11 Years) [Full Trial] | Consumption of N8-GP During Prophylaxis (U/kg Per Year) | 6760.4 U/kg/year | Standard Deviation 181.8 |
Secondary
Consumption of N8-GP Per Bleeding Episode (Number of Injections)
The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed.
Time frame: Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)
Population: Results were based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Consumption of N8-GP Per Bleeding Episode (Number of Injections) | 1.9 Number of injections | Standard Deviation 1.5 |
| Older Children (6 - 11 Years) [Main Trial] | Consumption of N8-GP Per Bleeding Episode (Number of Injections) | 1.6 Number of injections | Standard Deviation 0.9 |
| Younger Children (0 - 5 Years) [Full Trial] | Consumption of N8-GP Per Bleeding Episode (Number of Injections) | 1.6 Number of injections | Standard Deviation 1.3 |
| Older Children (6 - 11 Years) [Full Trial] | Consumption of N8-GP Per Bleeding Episode (Number of Injections) | 1.5 Number of injections | Standard Deviation 1.1 |
Secondary
Consumption of N8-GP Per Bleeding Episode (U/kg)
The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed.
Time frame: Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)
Population: Results were based on FAS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Consumption of N8-GP Per Bleeding Episode (U/kg) | 123 IU/kg/bleed | Standard Deviation 104.9 |
| Older Children (6 - 11 Years) [Main Trial] | Consumption of N8-GP Per Bleeding Episode (U/kg) | 99 IU/kg/bleed | Standard Deviation 54.4 |
| Younger Children (0 - 5 Years) [Full Trial] | Consumption of N8-GP Per Bleeding Episode (U/kg) | 102.8 IU/kg/bleed | Standard Deviation 81 |
| Older Children (6 - 11 Years) [Full Trial] | Consumption of N8-GP Per Bleeding Episode (U/kg) | 91 IU/kg/bleed | Standard Deviation 58.3 |
Secondary
Frequency of Adverse Events Including Serious Adverse Events Reported During the Trial Period
The frequency of adverse events including serious adverse events reported during the main and extension phase of the trial. The data presented is the rate of AE i.e. number of AEs per patient years of exposue.
Time frame: Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)
Population: Results were based on SAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Frequency of Adverse Events Including Serious Adverse Events Reported During the Trial Period | 4.87 Events per patient years of exposure |
| Older Children (6 - 11 Years) [Main Trial] | Frequency of Adverse Events Including Serious Adverse Events Reported During the Trial Period | 4.74 Events per patient years of exposure |
| Younger Children (0 - 5 Years) [Full Trial] | Frequency of Adverse Events Including Serious Adverse Events Reported During the Trial Period | 3.09 Events per patient years of exposure |
| Older Children (6 - 11 Years) [Full Trial] | Frequency of Adverse Events Including Serious Adverse Events Reported During the Trial Period | 2.45 Events per patient years of exposure |
Secondary
Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None
Haemostatic effect of N8-GP for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Evaluation during trial was done by patient and/or parent(s)/caregiver 8 hours after first injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hours after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but possibly requiring more than one injection for complete resolution; Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection, but usually requiring more than one injection; None: No improvement, or worsening of symptoms.
Time frame: Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)
Population: Results were based on full analysis set (FAS). All trial patients allocated to treatment, for which at least one of the pharmacokinetic or efficacy endpoints was assessed, were included in the FAS.
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | None | 1 Bleeding episodes |
| Younger Children (0 - 5 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Good | 13 Bleeding episodes |
| Younger Children (0 - 5 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Missing | 1 Bleeding episodes |
| Younger Children (0 - 5 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Moderate | 4 Bleeding episodes |
| Younger Children (0 - 5 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Excellent | 11 Bleeding episodes |
| Older Children (6 - 11 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Moderate | 7 Bleeding episodes |
| Older Children (6 - 11 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | None | 0 Bleeding episodes |
| Older Children (6 - 11 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Missing | 2 Bleeding episodes |
| Older Children (6 - 11 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Good | 19 Bleeding episodes |
| Older Children (6 - 11 Years) [Main Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Excellent | 12 Bleeding episodes |
| Younger Children (0 - 5 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Moderate | 9 Bleeding episodes |
| Younger Children (0 - 5 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Excellent | 47 Bleeding episodes |
| Younger Children (0 - 5 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Good | 48 Bleeding episodes |
| Younger Children (0 - 5 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | None | 2 Bleeding episodes |
| Younger Children (0 - 5 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Missing | 2 Bleeding episodes |
| Older Children (6 - 11 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | None | 2 Bleeding episodes |
| Older Children (6 - 11 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Good | 74 Bleeding episodes |
| Older Children (6 - 11 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Excellent | 96 Bleeding episodes |
| Older Children (6 - 11 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Moderate | 44 Bleeding episodes |
| Older Children (6 - 11 Years) [Full Trial] | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None | Missing | 6 Bleeding episodes |
Secondary
Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for N8-GP
The incremental recovery was defined as the peak level recorded 60 min after end of injection and dose-normalised. It was calculated as (FVIII:C activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with product specific calibrator (PSS) as calibrator was used.
Time frame: From 1 hour prior to and up to 96 hours after initial administration of N8-GP
Population: Results were based on FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for N8-GP | 0.018 (IU/mL)/(U/kg) |
| Older Children (6 - 11 Years) [Main Trial] | Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for N8-GP | 0.020 (IU/mL)/(U/kg) |
Secondary
Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for Previous FVIII Product
The incremental recovery was defined as the increase in plasma FVIII activity per IU/kg of factor administered recorded 60 minutes after end of injection. It was calculated as (Factor VIII procoagulant \[FVIII:C\] activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with normal human plasma (NHP) as calibrator was used.
Time frame: 2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product
Population: Results were based on FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for Previous FVIII Product | 0.017 (IU/mL)/(U/kg) |
| Older Children (6 - 11 Years) [Main Trial] | Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for Previous FVIII Product | 0.022 (IU/mL)/(U/kg) |
Secondary
Number of Bleeding Episodes During Prophylactic Treatment With N8-GP (Annualised Bleeding Rate)
The number of bleeding episodes per year reported during the prophylactic treatment with N8-GP.
Time frame: Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)
Population: Results were based on FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Number of Bleeding Episodes During Prophylactic Treatment With N8-GP (Annualised Bleeding Rate) | 1.94 bleeds/patient/year |
| Older Children (6 - 11 Years) [Main Trial] | Number of Bleeding Episodes During Prophylactic Treatment With N8-GP (Annualised Bleeding Rate) | 1.97 bleeds/patient/year |
| Younger Children (0 - 5 Years) [Full Trial] | Number of Bleeding Episodes During Prophylactic Treatment With N8-GP (Annualised Bleeding Rate) | 0.61 bleeds/patient/year |
| Older Children (6 - 11 Years) [Full Trial] | Number of Bleeding Episodes During Prophylactic Treatment With N8-GP (Annualised Bleeding Rate) | 0.93 bleeds/patient/year |
Secondary
Terminal Half-life Evaluated for N8-GP
t½ = ln(2) / λz, where λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the LLOQ. This was estimated using time points from 6h to 96h. A chromogenic assay with PSS as calibrator was used.
Time frame: From 1 hour prior to and up to 96 hours after initial administration of N8-GP
Population: Results were based on FAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Terminal Half-life Evaluated for N8-GP | 13.6 hours | Geometric Coefficient of Variation 20.4 |
| Older Children (6 - 11 Years) [Main Trial] | Terminal Half-life Evaluated for N8-GP | 14.1 hours | Geometric Coefficient of Variation 25 |
Secondary
Terminal Half-life Evaluated for Previous FVIII Product
t½ = ln(2) / λz, where t½ is terminal half-life and λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the lower limit of quantification (LLOQ). This was estimated using time points from 1h to 30h. A chromogenic assay with PSS as calibrator was used.
Time frame: 2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product
Population: Results were based on FAS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Younger Children (0 - 5 Years) [Main Trial] | Terminal Half-life Evaluated for Previous FVIII Product | 7.2 hours | Geometric Coefficient of Variation 20.1 |
| Older Children (6 - 11 Years) [Main Trial] | Terminal Half-life Evaluated for Previous FVIII Product | 7.5 hours | Geometric Coefficient of Variation 19.1 |