Haemophilia A
Conditions
Brief summary
The study investigates how well the medicine called turoctocog alfa pegol (N8-GP) works in previously treated Chinese patients with severe haemophilia A. Participants will be treated with N8-GP. This is a medicine that doctors can already prescribe in other countries. The medicine will be injected into a vein (intravenous injections) and blood samples will be collected. The study will last for about 7-8 months. Participants will have between 8 and 15 visits to the clinic and possibly a number of phone calls with the study doctor.
Interventions
N8-GP will be injected into a vein (intravenous injections) every 4 days in at least 28 weeks
Sponsors
Novo Nordisk A/S
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial. * Male Chinese patient with severe congenital haemophilia A with a FVIII activity below 1% according to medical records. * Aged greater than or equal to 12 years at the time of signing informed consent. * History of at least 150 exposure days (EDs) to other FVIII products. * The patient and/or caregiver is capable of assessing a bleeding episode, keeping a diary, performing home treatment of bleeding episodes and otherwise following the trial procedures at the discretion of the investigator.
Exclusion criteria
* Known or suspected hypersensitivity to trial product or related products. * Previous participation in this trial. Participation is defined as signed informed consent. * Participation in any clinical trial of an approved or non-approved investigational medicinal product within 5 half-lives or 30 days from screening, whichever is longer. * Known history of FVIII inhibitors based on existing medical records, laboratory report reviews and patient and/or caregiver interviews. * Current FVIII inhibitors greater than or equal to 0.6 BU. * Congenital or acquired coagulation disorder other than haemophilia According to medical records. * HIV positive, defined by medical records, with CD4+ count less than or equal 200/L and a viral load greater than 200 particles/μl or greater than 400000 copies/mL within 6 months of the trial entry. If the data are not available in medical records within last 6 months, then the test must be performed at screening visit. * Previous significant thromboembolic events (e.g. myocardial infarction, cerebrovascular disease or deep venous thrombosis) as defined by available medical records. * Hepatic dysfunction defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater than 3 times limit of normal combined with total bilirubin greater than 1.5 times the upper limit of normal at screening, as defined by central laboratory * Renal impairment defined as estimated glomerular filtration rate (eGFR) below or equal to 30 mL/min/1.73 m\^2 for serum creatinine measured at screening, as defined by central laboratory. * Platelet count below 50×109/L at screening based on central laboratory values at screening. * Ongoing immune modulating or chemotherapeutic medication. * Any disorder, except for conditions associated with haemophilia A, which in the investigator's opinion might jeopardise the patient's safety or compliance with the protocol. * Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Bleeding Episodes Per Year (Annualised Bleeding Rate) | From start of treatment (Week 0) until Week 28 | Number of bleeding episodes per year (Annualised Bleeding Rate) data is reported. Annualised bleeding rate (ABR) is the number of bleeding episodes per year. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | From start of treatment (Week 0) until Week 28 | 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 participant and/or parent(s)/caregiver within approximately 8 hours after a single injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hrs after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hrs 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. |
| Consumption of N8-GP for Prophylaxis | From start of treatment (Week 0) until Week 28 | The mean consumption of N8-GP for prophylaxis per year per participant was reported and it was measured in international units per kilogram per year (IU/kg/year). |
| FVIII Trough Activity During Prophylaxis | From start of treatment (Week 0) (excluding the first exposure) until Week 28 | Trough levels of FVIII was reported for all participnats who received prophylaxis treatment. Chromogenic assay was performed with N8-GP product specific standard (PSS) as a calibrator. The analysis is based on a mixed model on the log transformed plasma FVIII activity with age group as fixed effect and participant as a random effect. The mean trough is presented back-transformed to the natural scale. |
| Percentage of Participants With Incidence Rate of Confirmed FVIII Inhibitors ≥0.6 BU | From start of treatment (Week 0) until Week 28 | Percentage of participants who developed inhibitory antibodies against FVIII was presented. A participant was said to have FVIII-inhibitors if two consecutive tests, preferably within 2 weeks, were positive (greater than or equal to (≥) 0.6 bethesda unit (BU)). For the calculation of the inhibitor rate the numerator was included for all participants with neutralising antibodies while the denominator was included for all participants with a minimum of 50 exposures plus any participants with less than 50 exposures but with neutralising inhibitor. |
| Number of Adverse Events (AEs) | From start of treatment (Week 0) until end of trial (Week 32) | An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. All presented AEs are treatment-emergent. A treatment-emergent adverse event was defined as an event with onset after first N8-GP administration. |
| Number of Serious Adverse Events (SAEs) | From start of treatment (Week 0) until end of trial (Week 32) | A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, or is life-threatening, or requires inpatient hospitalization or causes prolongation of existing hospitalization results in persistent or significant disability/incapacity, or may have caused a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. All presented SAEs are treatment-emergent (any serious adverse events which occurred after trial product administration). |
| Incremental Recovery (IR) | 30 min post-injection at Week 0, Week 28 | The incremental recovery was calculated by subtracting the FVIII activity (IU/mL) measured in plasma at time 0 from that measured at time 30 min after dosing and dividing this difference by the dose injected at time 0 expressed as IU/kg body weight. FVIII activity was measured with a chromogenic assay. |
| FVIII Activity 30 Min Post-injection (C30min) | 30 min post-injection at Week 0, Week 28 | FVIII plasma activity was measured after 30 mins of injection. FVIII activity was measured with a chromogenic assay. |
| FVIII Trough Activity 96 h Post-injection (C96h) | Single-dose: 96 h ± 8 h post-injection at Week 0, Steady-state: 96 h ± 8 h post-injection at Week 28 | FVIII plasma activity was measured after 96 h of injection. This was measured at two time points Week 0 and Week 28 during the study. Chromogenic assay was performed. |
| Area Under the Curve (AUC0-inf) | 0-96 hours post-injection at Week 0 and Week 28 | Area under the plasma activity versus time profile from time zero to infinity (AUC0-inf) was measured. |
| Number of Injections Needed to Treat Bleeding Episodes | From start of treatment (Week 0) until Week 28 | The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed was reported. |
| Area Under the Curve (0-96h) | 0-96 hours post-injection at Week 0 and Week 28 | Area under the plasma activity versus time profile from time zero to 96 hours (AUC0-96h) was measured. |
| Accumulation Ratio | 0-96 hours post-injection on Week 28 | Accumulation ratio was calculated as AUC(0-96h) at steady state/AUC(0-96h) at single dose. AUC(0-96) is the area under the plasma activity versus time profile from time zero to 96 hours. |
| Terminal Half-life (t½) | 0-96 hours post-injection on Week 0 and Week 28 | Terminal half life was calculated as ln(2)/λz; where λz is the terminal elimination rate constant. The terminal elimination rate constant was estimated using linear regression on the terminal part of the log (activity) versus time profile. |
| Clearance (CL) | Single-dose: 0-96 h post-injection at Week 0, Steady-state: 0-96 h post-injection at Week 28 | Clearance (CL) of drug after intravenous administration was reported. Clearance was calculated using the formula CL= Dose / AUC(0-inf) for single dose and CL= Dose / AUC(0-96) h for steady state. |
| Apparent Volume of Distribution (Vz) Based on the Terminal Phase | 0-96 hours post-injection on Week 0 and Week 28 | Apparent volume of distribution (Vz) based on the terminal phase was measured. Apparent volume of distribution was calculated using formula: total plasma clearance divided by terminal elimination rate constant (Vz= CL/λz). |
| Apparent Volume of Distribution (Vss) Based on Steady-state | 0-96 h post-injection at Week 28 | Apparent volume of distribution (Vss) at steady-state was measured. Apparent volume of distribution (Vss) was calculated using formula: total plasma clearance multiplied by mean residence time (Vss=CL\*MRT). |
| Extrapolated Area Under the Curve (AUC Percent [%] Extrap | 0-96 hours post-injection on Week 0 and Week 28 | Percentage of AUC(0-inf) determined by extrapolation. It was calulating using formula: Area under the plasma activity versus time profile from given measurable time to infinity (AUCt-inf)/Area under the plasma activity versus time profile from time zero to infinity (AUC0-inf). |
| Mean Residence Time | 0-96 hours post-injection on Week 0 and Week 28 | Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). (AUMC \[0-inf\]) is the area under the first moment plasma concentration-time curve from time 0 to infinity. |
| Terminal Elimination Rate Constant (λz) | 0-96 hours post-injection on Week 0 and Week 28 | The terminal elimination rate constant was estimated using linear regression on the terminal part of the log(activity) versus time profile. |
| Area Under the Curve (0-t) | 0-96 hours post-injection at Week 0 and Week 28 | Area under the plasma activity versus time profile from time zero to last measurable activity (AUC0-t) was measured. |
Countries
China
Participant flow
Recruitment details
A total of 36 Chinese participants with a severe haemophilia A were recruited in this trial. The trial was conducted at 8 sites in China mainland.
Participants by arm
| Arm | Count |
|---|---|
| Adolescents (12-17 Years) Participants with haemophilia A aged 12-17 years with greater than or equal to (≥) 150 exposure days to other FVIII product received one single bolus dose of 50 international unit per Kilogram (IU/kg) of turoctocog alfa pegol (N8-GP), administered intravenously (IV) every 4th day (96 hours) or twice weekly (investigator's discretion). All bleeds were to be treated with doses between 20-75 IU/kg according to the severity and location of the bleeding episode. | 13 |
| Adults (18-70 Years) Participants with haemophilia A aged 18-70 years with ≥150 exposure days to other FVIII product received one single bolus dose of 50 IU/kg of turoctocog alfa pegol (N8-GP), administered IV every 4th day (96 hours) or twice weekly (investigator's discretion). All bleeds were to be treated with doses between 20-75 IU/kg according to the severity and location of the bleeding episode. | 23 |
| Total | 36 |
Baseline characteristics
| Characteristic | Adolescents (12-17 Years) | Adults (18-70 Years) | Total |
|---|---|---|---|
| Age, Continuous | 13.7 Years STANDARD_DEVIATION 1.7 | 28.7 Years STANDARD_DEVIATION 9.2 | 23.3 Years STANDARD_DEVIATION 10.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 23 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 23 Participants | 36 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 23 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 23 |
| other Total, other adverse events | 7 / 13 | 4 / 23 |
| serious Total, serious adverse events | 0 / 13 | 0 / 23 |
Outcome results
Primary
Number of Bleeding Episodes Per Year (Annualised Bleeding Rate)
Number of bleeding episodes per year (Annualised Bleeding Rate) data is reported. Annualised bleeding rate (ABR) is the number of bleeding episodes per year.
Time frame: From start of treatment (Week 0) until Week 28
Population: Results were based on the FAS which included all participants exposed to N8-GP in this trial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adolescents (12-17 Years) | Number of Bleeding Episodes Per Year (Annualised Bleeding Rate) | 0.00 Bleeding episodes per year |
| Adults (18-70 Years) | Number of Bleeding Episodes Per Year (Annualised Bleeding Rate) | 0.00 Bleeding episodes per year |
Secondary
Accumulation Ratio
Accumulation ratio was calculated as AUC(0-96h) at steady state/AUC(0-96h) at single dose. AUC(0-96) is the area under the plasma activity versus time profile from time zero to 96 hours.
Time frame: 0-96 hours post-injection on Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Overall number of partianalyzed = Number of participants with available data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Adolescents (12-17 Years) | Accumulation Ratio | 1.152 Ratio of AUC | Geometric Coefficient of Variation 19.682 |
| Adults (18-70 Years) | Accumulation Ratio | 1.086 Ratio of AUC | Geometric Coefficient of Variation 53.085 |
Secondary
Apparent Volume of Distribution (Vss) Based on Steady-state
Apparent volume of distribution (Vss) at steady-state was measured. Apparent volume of distribution (Vss) was calculated using formula: total plasma clearance multiplied by mean residence time (Vss=CL\*MRT).
Time frame: 0-96 h post-injection at Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Overall number of partianalyzed = Number of participants with available data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Adolescents (12-17 Years) | Apparent Volume of Distribution (Vss) Based on Steady-state | 34.511 milliter per kilogram (mL/kg) | Geometric Coefficient of Variation 5.727 |
| Adults (18-70 Years) | Apparent Volume of Distribution (Vss) Based on Steady-state | 39.786 milliter per kilogram (mL/kg) | Geometric Coefficient of Variation 28.558 |
Secondary
Apparent Volume of Distribution (Vz) Based on the Terminal Phase
Apparent volume of distribution (Vz) based on the terminal phase was measured. Apparent volume of distribution was calculated using formula: total plasma clearance divided by terminal elimination rate constant (Vz= CL/λz).
Time frame: 0-96 hours post-injection on Week 0 and Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Apparent Volume of Distribution (Vz) Based on the Terminal Phase | Week 0 | 45.098 milliter per kilogram (mL/kg) | Geometric Coefficient of Variation 24.375 |
| Adolescents (12-17 Years) | Apparent Volume of Distribution (Vz) Based on the Terminal Phase | Week 28 | 36.673 milliter per kilogram (mL/kg) | Geometric Coefficient of Variation 4.042 |
| Adults (18-70 Years) | Apparent Volume of Distribution (Vz) Based on the Terminal Phase | Week 0 | 45.165 milliter per kilogram (mL/kg) | Geometric Coefficient of Variation 34.649 |
| Adults (18-70 Years) | Apparent Volume of Distribution (Vz) Based on the Terminal Phase | Week 28 | 41.878 milliter per kilogram (mL/kg) | Geometric Coefficient of Variation 27.534 |
Secondary
Area Under the Curve (0-96h)
Area under the plasma activity versus time profile from time zero to 96 hours (AUC0-96h) was measured.
Time frame: 0-96 hours post-injection at Week 0 and Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Area Under the Curve (0-96h) | Week 0 | 30.509 h*(IU/mL) | Geometric Coefficient of Variation 19.989 |
| Adolescents (12-17 Years) | Area Under the Curve (0-96h) | Week 28 | 36.428 h*(IU/mL) | Geometric Coefficient of Variation 4.251 |
| Adults (18-70 Years) | Area Under the Curve (0-96h) | Week 0 | 32.269 h*(IU/mL) | Geometric Coefficient of Variation 26.558 |
| Adults (18-70 Years) | Area Under the Curve (0-96h) | Week 28 | 36.398 h*(IU/mL) | Geometric Coefficient of Variation 27.168 |
Secondary
Area Under the Curve (0-t)
Area under the plasma activity versus time profile from time zero to last measurable activity (AUC0-t) was measured.
Time frame: 0-96 hours post-injection at Week 0 and Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Area Under the Curve (0-t) | Week 0 | 30.578 h*(IU/mL) | Geometric Coefficient of Variation 19.999 |
| Adolescents (12-17 Years) | Area Under the Curve (0-t) | Week 28 | 36.467 h*(IU/mL) | Geometric Coefficient of Variation 4.292 |
| Adults (18-70 Years) | Area Under the Curve (0-t) | Week 0 | 32.300 h*(IU/mL) | Geometric Coefficient of Variation 26.565 |
| Adults (18-70 Years) | Area Under the Curve (0-t) | Week 28 | 36.406 h*(IU/mL) | Geometric Coefficient of Variation 27.173 |
Secondary
Area Under the Curve (AUC0-inf)
Area under the plasma activity versus time profile from time zero to infinity (AUC0-inf) was measured.
Time frame: 0-96 hours post-injection at Week 0 and Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Area Under the Curve (AUC0-inf) | Week 0 | 31.556 h*(IU/mL) | Geometric Coefficient of Variation 20.1 |
| Adolescents (12-17 Years) | Area Under the Curve (AUC0-inf) | Week 28 | 37.274 h*(IU/mL) | Geometric Coefficient of Variation 4.541 |
| Adults (18-70 Years) | Area Under the Curve (AUC0-inf) | Week 0 | 33.650 h*(IU/mL) | Geometric Coefficient of Variation 26.123 |
| Adults (18-70 Years) | Area Under the Curve (AUC0-inf) | Week 28 | 37.952 h*(IU/mL) | Geometric Coefficient of Variation 28.03 |
Secondary
Clearance (CL)
Clearance (CL) of drug after intravenous administration was reported. Clearance was calculated using the formula CL= Dose / AUC(0-inf) for single dose and CL= Dose / AUC(0-96) h for steady state.
Time frame: Single-dose: 0-96 h post-injection at Week 0, Steady-state: 0-96 h post-injection at Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Clearance (CL) | Week 0 | 1.636 milliter per hour per kilogram (mL/h/kg) | Geometric Coefficient of Variation 17.092 |
| Adolescents (12-17 Years) | Clearance (CL) | Week 28 | 1.434 milliter per hour per kilogram (mL/h/kg) | Geometric Coefficient of Variation 4.488 |
| Adults (18-70 Years) | Clearance (CL) | Week 0 | 1.550 milliter per hour per kilogram (mL/h/kg) | Geometric Coefficient of Variation 29.123 |
| Adults (18-70 Years) | Clearance (CL) | Week 28 | 1.434 milliter per hour per kilogram (mL/h/kg) | Geometric Coefficient of Variation 25.335 |
Secondary
Consumption of N8-GP for Prophylaxis
The mean consumption of N8-GP for prophylaxis per year per participant was reported and it was measured in international units per kilogram per year (IU/kg/year).
Time frame: From start of treatment (Week 0) until Week 28
Population: Results were based on the FAS which included all participants exposed to N8-GP in this trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adolescents (12-17 Years) | Consumption of N8-GP for Prophylaxis | 4909.5 IU/kg/year | Standard Deviation 252 |
| Adults (18-70 Years) | Consumption of N8-GP for Prophylaxis | 4873.9 IU/kg/year | Standard Deviation 237.6 |
Secondary
Extrapolated Area Under the Curve (AUC Percent [%] Extrap
Percentage of AUC(0-inf) determined by extrapolation. It was calulating using formula: Area under the plasma activity versus time profile from given measurable time to infinity (AUCt-inf)/Area under the plasma activity versus time profile from time zero to infinity (AUC0-inf).
Time frame: 0-96 hours post-injection on Week 0 and Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Extrapolated Area Under the Curve (AUC Percent [%] Extrap | Week 0 | 2.847 Percentage of AUC | Geometric Coefficient of Variation 47.917 |
| Adolescents (12-17 Years) | Extrapolated Area Under the Curve (AUC Percent [%] Extrap | Week 28 | 2.143 Percentage of AUC | Geometric Coefficient of Variation 17.743 |
| Adults (18-70 Years) | Extrapolated Area Under the Curve (AUC Percent [%] Extrap | Week 0 | 3.392 Percentage of AUC | Geometric Coefficient of Variation 63.42 |
| Adults (18-70 Years) | Extrapolated Area Under the Curve (AUC Percent [%] Extrap | Week 28 | 3.424 Percentage of AUC | Geometric Coefficient of Variation 65.849 |
Secondary
FVIII Activity 30 Min Post-injection (C30min)
FVIII plasma activity was measured after 30 mins of injection. FVIII activity was measured with a chromogenic assay.
Time frame: 30 min post-injection at Week 0, Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | FVIII Activity 30 Min Post-injection (C30min) | Week 0 | 1.178 IU/mL | Geometric Coefficient of Variation 24.531 |
| Adolescents (12-17 Years) | FVIII Activity 30 Min Post-injection (C30min) | Week 28 | 1.557 IU/mL | Geometric Coefficient of Variation 0.646 |
| Adults (18-70 Years) | FVIII Activity 30 Min Post-injection (C30min) | Week 0 | 1.196 IU/mL | Geometric Coefficient of Variation 27.304 |
| Adults (18-70 Years) | FVIII Activity 30 Min Post-injection (C30min) | Week 28 | 1.302 IU/mL | Geometric Coefficient of Variation 21.521 |
Secondary
FVIII Trough Activity 96 h Post-injection (C96h)
FVIII plasma activity was measured after 96 h of injection. This was measured at two time points Week 0 and Week 28 during the study. Chromogenic assay was performed.
Time frame: Single-dose: 96 h ± 8 h post-injection at Week 0, Steady-state: 96 h ± 8 h post-injection at Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | FVIII Trough Activity 96 h Post-injection (C96h) | Week 0 | 0.033 IU/mL | Geometric Coefficient of Variation 36.048 |
| Adolescents (12-17 Years) | FVIII Trough Activity 96 h Post-injection (C96h) | Week 28 | 0.032 IU/mL | Geometric Coefficient of Variation 14.616 |
| Adults (18-70 Years) | FVIII Trough Activity 96 h Post-injection (C96h) | Week 0 | 0.039 IU/mL | Geometric Coefficient of Variation 44.608 |
| Adults (18-70 Years) | FVIII Trough Activity 96 h Post-injection (C96h) | Week 28 | 0.045 IU/mL | Geometric Coefficient of Variation 58.02 |
Secondary
FVIII Trough Activity During Prophylaxis
Trough levels of FVIII was reported for all participnats who received prophylaxis treatment. Chromogenic assay was performed with N8-GP product specific standard (PSS) as a calibrator. The analysis is based on a mixed model on the log transformed plasma FVIII activity with age group as fixed effect and participant as a random effect. The mean trough is presented back-transformed to the natural scale.
Time frame: From start of treatment (Week 0) (excluding the first exposure) until Week 28
Population: Results were based on the FAS which included all participants exposed to N8-GP in this trial.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Adolescents (12-17 Years) | FVIII Trough Activity During Prophylaxis | 0.032 International unit per milliliter(IU/mL) |
| Adults (18-70 Years) | FVIII Trough Activity During Prophylaxis | 0.034 International unit per milliliter(IU/mL) |
Secondary
Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and 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 participant and/or parent(s)/caregiver within approximately 8 hours after a single injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hrs after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hrs 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: From start of treatment (Week 0) until Week 28
Population: Results were based on the FAS which included all participants exposed to N8-GP in this trial.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adolescents (12-17 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | Good | 3 Bleeding Episodes |
| Adolescents (12-17 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | None | 0 Bleeding Episodes |
| Adolescents (12-17 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | Moderate | 3 Bleeding Episodes |
| Adolescents (12-17 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | Missing | 0 Bleeding Episodes |
| Adolescents (12-17 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | Excellent | 18 Bleeding Episodes |
| Adults (18-70 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | Missing | 0 Bleeding Episodes |
| Adults (18-70 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | Excellent | 22 Bleeding Episodes |
| Adults (18-70 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | Good | 6 Bleeding Episodes |
| Adults (18-70 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | Moderate | 0 Bleeding Episodes |
| Adults (18-70 Years) | Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None) | None | 0 Bleeding Episodes |
Secondary
Incremental Recovery (IR)
The incremental recovery was calculated by subtracting the FVIII activity (IU/mL) measured in plasma at time 0 from that measured at time 30 min after dosing and dividing this difference by the dose injected at time 0 expressed as IU/kg body weight. FVIII activity was measured with a chromogenic assay.
Time frame: 30 min post-injection at Week 0, Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Incremental Recovery (IR) | Week 28 | 0.029 (IU/mL)/(IU/kg) | Geometric Coefficient of Variation 1.443 |
| Adolescents (12-17 Years) | Incremental Recovery (IR) | Week 0 | 0.023 (IU/mL)/(IU/kg) | Geometric Coefficient of Variation 28.107 |
| Adults (18-70 Years) | Incremental Recovery (IR) | Week 28 | 0.024 (IU/mL)/(IU/kg) | Geometric Coefficient of Variation 23.535 |
| Adults (18-70 Years) | Incremental Recovery (IR) | Week 0 | 0.023 (IU/mL)/(IU/kg) | Geometric Coefficient of Variation 28.367 |
Secondary
Mean Residence Time
Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). (AUMC \[0-inf\]) is the area under the first moment plasma concentration-time curve from time 0 to infinity.
Time frame: 0-96 hours post-injection on Week 0 and Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Mean Residence Time | Week 0 | 27.101 hour | Geometric Coefficient of Variation 13.4 |
| Adolescents (12-17 Years) | Mean Residence Time | Week 28 | 24.070 hour | Geometric Coefficient of Variation 4.347 |
| Adults (18-70 Years) | Mean Residence Time | Week 0 | 27.941 hour | Geometric Coefficient of Variation 21.114 |
| Adults (18-70 Years) | Mean Residence Time | Week 28 | 27.739 hour | Geometric Coefficient of Variation 22.177 |
Secondary
Number of Adverse Events (AEs)
An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. All presented AEs are treatment-emergent. A treatment-emergent adverse event was defined as an event with onset after first N8-GP administration.
Time frame: From start of treatment (Week 0) until end of trial (Week 32)
Population: Results were based on the safety analysis set (SAS) which included all participants exposed to N8-GP in this trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adolescents (12-17 Years) | Number of Adverse Events (AEs) | 15 Events |
| Adults (18-70 Years) | Number of Adverse Events (AEs) | 25 Events |
Secondary
Number of Injections Needed to Treat Bleeding Episodes
The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed was reported.
Time frame: From start of treatment (Week 0) until Week 28
Population: Results were based on the FAS which included all participants exposed to N8-GP in this trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adolescents (12-17 Years) | Number of Injections Needed to Treat Bleeding Episodes | 2 Injections per bleed | Standard Deviation 0.8 |
| Adults (18-70 Years) | Number of Injections Needed to Treat Bleeding Episodes | 1 Injections per bleed | Standard Deviation 0.3 |
Secondary
Number of Serious Adverse Events (SAEs)
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, or is life-threatening, or requires inpatient hospitalization or causes prolongation of existing hospitalization results in persistent or significant disability/incapacity, or may have caused a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. All presented SAEs are treatment-emergent (any serious adverse events which occurred after trial product administration).
Time frame: From start of treatment (Week 0) until end of trial (Week 32)
Population: Results were based on the SAS which included all participants exposed to N8-GP in this trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adolescents (12-17 Years) | Number of Serious Adverse Events (SAEs) | 0 Events |
| Adults (18-70 Years) | Number of Serious Adverse Events (SAEs) | 0 Events |
Secondary
Percentage of Participants With Incidence Rate of Confirmed FVIII Inhibitors ≥0.6 BU
Percentage of participants who developed inhibitory antibodies against FVIII was presented. A participant was said to have FVIII-inhibitors if two consecutive tests, preferably within 2 weeks, were positive (greater than or equal to (≥) 0.6 bethesda unit (BU)). For the calculation of the inhibitor rate the numerator was included for all participants with neutralising antibodies while the denominator was included for all participants with a minimum of 50 exposures plus any participants with less than 50 exposures but with neutralising inhibitor.
Time frame: From start of treatment (Week 0) until Week 28
Population: Results were based on the FAS which included all participants exposed to N8-GP in this trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adolescents (12-17 Years) | Percentage of Participants With Incidence Rate of Confirmed FVIII Inhibitors ≥0.6 BU | 0.00 Percentage of participants |
| Adults (18-70 Years) | Percentage of Participants With Incidence Rate of Confirmed FVIII Inhibitors ≥0.6 BU | 0.00 Percentage of participants |
Secondary
Terminal Elimination Rate Constant (λz)
The terminal elimination rate constant was estimated using linear regression on the terminal part of the log(activity) versus time profile.
Time frame: 0-96 hours post-injection on Week 0 and Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Terminal Elimination Rate Constant (λz) | Week 0 | 0.036 1/hour | Geometric Coefficient of Variation 13.526 |
| Adolescents (12-17 Years) | Terminal Elimination Rate Constant (λz) | Week 28 | 0.039 1/hour | Geometric Coefficient of Variation 5.749 |
| Adults (18-70 Years) | Terminal Elimination Rate Constant (λz) | Week 0 | 0.034 1/hour | Geometric Coefficient of Variation 18.083 |
| Adults (18-70 Years) | Terminal Elimination Rate Constant (λz) | Week 28 | 0.034 1/hour | Geometric Coefficient of Variation 16.862 |
Secondary
Terminal Half-life (t½)
Terminal half life was calculated as ln(2)/λz; where λz is the terminal elimination rate constant. The terminal elimination rate constant was estimated using linear regression on the terminal part of the log (activity) versus time profile.
Time frame: 0-96 hours post-injection on Week 0 and Week 28
Population: The PK analysis set included sub-set of participants from FAS who were included for PK assessments. Number analyzed = Number of participants with available data for specific timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adolescents (12-17 Years) | Terminal Half-life (t½) | Week 0 | 19.106 hour (h) | Geometric Coefficient of Variation 14.019 |
| Adolescents (12-17 Years) | Terminal Half-life (t½) | Week 28 | 17.729 hour (h) | Geometric Coefficient of Variation 5.568 |
| Adults (18-70 Years) | Terminal Half-life (t½) | Week 0 | 20.200 hour (h) | Geometric Coefficient of Variation 20.422 |
| Adults (18-70 Years) | Terminal Half-life (t½) | Week 28 | 20.238 hour (h) | Geometric Coefficient of Variation 18.882 |