Hemophilia B
Conditions
Brief summary
The sample size of 12 male Chinese subjects are based on the CFDA requirement for a China PK study and to support the registration in China.
Interventions
DRUGBENEFIX
Single dose of 50 IU/kg of BeneFIX by intravenous infusion within 10 minutes.
Sponsors
Pfizer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male Chinese subjects 6 years or older (weight ≥20kg) with moderate to severe hemophilia B (Factor IX activity ≤2%). * Subjects should not have received an infusion of any Factor IX products for at least 4 days before the administration of BeneFIX on Day 1. * Subjects must be in a non-bleeding state before the administration of BeneFIX on Day 1.
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) disease or clinical findings at Screening. * Diagnosed with any other bleeding disorder in addition to hemophilia B. * Current FIX inhibitor or history of FIX inhibitor (defined as \> Upper Limit of Normal (ULN) of the reporting lab).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incremental Recovery | Pre-dose, 0.25, 0.5 and 1 hour post-dose | Incremental recovery: Increase in circulating increase in FIX activity for every IU of BeneFIX administered per kg of body weight. |
| Time to Reach Cmax (Tmax) | Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose | — |
| Volume of Distribution at Steady State (Vss) | Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state. |
| Terminal Phase Rate Constant (Kel) | Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose | Linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression. |
| Mean Residence Time (MRT) | Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose | AUMCinf/AUCinf, where AUMCinf is the area under the first moment curve from time 0 extrapolated to infinite time, calculated using the linear/log trapezoidal method. |
| Plasma Decay Half-Life (t½) | Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Systemic Clearance (CL) | Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose | CL is a quantitative measure of the rate at which a drug substance is removed from the body. |
| Maximum Observed Plasma Concentration (Cmax) | Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose | — |
| Area Under the Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) | Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose | — |
| Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinf) | Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Abnormal Clinical Laboratory Measurements (Without Regard to Baseline Abnormality) | Baseline up to 96 hours post-dose (Day 5 or early termination) | Clinical laboratory analysis tests included hematology, serium chemistry, prothrombin time and urianalysis. Numbers of subjects with laboratory test abnormalities without regard to baseline abnormality were reported. |
| Number of Participants With Vital Signs Post-Dose Data Met Criteria of Potential Clinical Concern (Without Regard to Baseline Abnormality) | Baseline up to 96 hours post-dose (Day 5 or early termination) | — |
| Number of Participants With Inhibitor Development | From the subject provided informed consent through and including 28 calendar days after the last administration of the study drug. | — |
| Number of Participants With Allergic Reactions | From the subject provided informed consent through and including 28 calendar days after the last administration of the study drug. | — |
| Number of Subjects With Thrombogenicity | From the subject provided informed consent through and including 28 calendar days after the last administration of the study drug. | — |
| Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Withdrawals Due to Adverse Events (AE) | From the subject provided informed consent through and including 28 calendar days after the last administration of the study drug. | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAE is defined as newly occurring or worsening after first dose. |
Countries
China
Participant flow
Recruitment details
Twelve (12) participants that were age 6 years or older (weight ≥20 kg) with moderate severe to severe hemophilia B (FIX activity ≤2%) were enrolled. Four (4) participants were at the younger age range of ≥6 and \<12 years; remaining participants were 12 years or older.
Pre-assignment details
Participants did not receive an infusion of any FIX products for at least 4 days and were required to be in a non-bleeding state before the administration of BeneFIX on Day 1.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants received a single dose of 50 IU/kg BeneFIX administered by IV infusion within 10 minutes at approximately 0800 hours (±2 hours) on Day 1. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 24.8 Years STANDARD_DEVIATION 15.4 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinf)
Time frame: Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose
Population: The PK parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinf) | 7.841 IU*hr/ml | Geometric Coefficient of Variation 16 |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinf) | 11.66 IU*hr/ml | Geometric Coefficient of Variation 15 |
Primary
Area Under the Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast)
Time frame: Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose
Population: The PK parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Area Under the Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) | 6.930 IU*hour/milliliter (IU*hr/mL) | Geometric Coefficient of Variation 18 |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Area Under the Concentration Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) | 9.707 IU*hour/milliliter (IU*hr/mL) | Geometric Coefficient of Variation 15 |
Primary
Incremental Recovery
Incremental recovery: Increase in circulating increase in FIX activity for every IU of BeneFIX administered per kg of body weight.
Time frame: Pre-dose, 0.25, 0.5 and 1 hour post-dose
Population: The PK parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Incremental Recovery | 0.7759 (IU/dL)/(IU/Kg) | Geometric Coefficient of Variation 26 |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Incremental Recovery | 0.8199 (IU/dL)/(IU/Kg) | Geometric Coefficient of Variation 17 |
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose
Population: The pharmacokinetics (PK) parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Maximum Observed Plasma Concentration (Cmax) | 0.3880 IU/milliliter (IU/mL) | Geometric Coefficient of Variation 26 |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Maximum Observed Plasma Concentration (Cmax) | 0.4226 IU/milliliter (IU/mL) | Geometric Coefficient of Variation 16 |
Primary
Mean Residence Time (MRT)
AUMCinf/AUCinf, where AUMCinf is the area under the first moment curve from time 0 extrapolated to infinite time, calculated using the linear/log trapezoidal method.
Time frame: Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose
Population: The PK parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Mean Residence Time (MRT) | 35.78 hours | Geometric Coefficient of Variation 14 |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Mean Residence Time (MRT) | 51.01 hours | Geometric Coefficient of Variation 16 |
Primary
Plasma Decay Half-Life (t½)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose
Population: The PK parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Plasma Decay Half-Life (t½) | 27.88 hours | Standard Deviation 4.4903 |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Plasma Decay Half-Life (t½) | 39.56 hours | Standard Deviation 7.3832 |
Primary
Systemic Clearance (CL)
CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Time frame: Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose
Population: The PK parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Systemic Clearance (CL) | 6.378 mL/hr/kg | Geometric Coefficient of Variation 16 |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Systemic Clearance (CL) | 4.291 mL/hr/kg | Geometric Coefficient of Variation 15 |
Primary
Terminal Phase Rate Constant (Kel)
Linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.
Time frame: Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose
Population: The PK parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Terminal Phase Rate Constant (Kel) | 0.02509 1/hr | Geometric Coefficient of Variation 16 |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Terminal Phase Rate Constant (Kel) | 0.01781 1/hr | Geometric Coefficient of Variation 20 |
Primary
Time to Reach Cmax (Tmax)
Time frame: Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose
Population: The PK parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Time to Reach Cmax (Tmax) | 0.500 hours |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Time to Reach Cmax (Tmax) | 0.375 hours |
Primary
Volume of Distribution at Steady State (Vss)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state.
Time frame: Pre-dose, 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72 and 96 hours post-dose
Population: The PK parameter analysis population was defined as all participants enrolled and treated who had at least 1 of the PK parameters of primary interest. All participants were included in the PK analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Volume of Distribution at Steady State (Vss) | 227.9 milliliter/kilogram (mL/kg) | Geometric Coefficient of Variation 20 |
| BeneFIX 50 IU/kg; Age Group:>=12 Years | Volume of Distribution at Steady State (Vss) | 218.8 milliliter/kilogram (mL/kg) | Geometric Coefficient of Variation 19 |
Secondary
Number of Participants With Abnormal Clinical Laboratory Measurements (Without Regard to Baseline Abnormality)
Clinical laboratory analysis tests included hematology, serium chemistry, prothrombin time and urianalysis. Numbers of subjects with laboratory test abnormalities without regard to baseline abnormality were reported.
Time frame: Baseline up to 96 hours post-dose (Day 5 or early termination)
Population: The safety analysis population included All participants who received at least 1 dose of BeneFIX.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Number of Participants With Abnormal Clinical Laboratory Measurements (Without Regard to Baseline Abnormality) | 12 Participants |
Secondary
Number of Participants With Allergic Reactions
Time frame: From the subject provided informed consent through and including 28 calendar days after the last administration of the study drug.
Population: The safety analysis population included All participants who received at least 1 dose of BeneFIX.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Number of Participants With Allergic Reactions | 0 Participants |
Secondary
Number of Participants With Inhibitor Development
Time frame: From the subject provided informed consent through and including 28 calendar days after the last administration of the study drug.
Population: The safety analysis population included All participants who received at least 1 dose of BeneFIX.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Number of Participants With Inhibitor Development | 0 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Withdrawals Due to Adverse Events (AE)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAE is defined as newly occurring or worsening after first dose.
Time frame: From the subject provided informed consent through and including 28 calendar days after the last administration of the study drug.
Population: The safety analysis set was defined as all participants who received at least 1 dose of BeneFIX.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious Adverse Events (SAE), and Withdrawals Due to Adverse Events (AE) | 0 Particpants |
Secondary
Number of Participants With Vital Signs Post-Dose Data Met Criteria of Potential Clinical Concern (Without Regard to Baseline Abnormality)
Time frame: Baseline up to 96 hours post-dose (Day 5 or early termination)
Population: The safety analysis population included All participants who received at least 1 dose of BeneFIX.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Number of Participants With Vital Signs Post-Dose Data Met Criteria of Potential Clinical Concern (Without Regard to Baseline Abnormality) | 1 Participants |
Secondary
Number of Subjects With Thrombogenicity
Time frame: From the subject provided informed consent through and including 28 calendar days after the last administration of the study drug.
Population: The safety analysis population included All participants who received at least 1 dose of BeneFIX.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BeneFIX 50 IU/kg; >=6 and <12 Years | Number of Subjects With Thrombogenicity | 0 Participants |