Hemophilia A
Conditions
Brief summary
The objective of this clinical study is to compare the pharmacokinetic parameters of 3000 IU Advate using one 3000 IU potency vial dissolved in 5 mL diluent with that of 3000 IU Advate using two vials of 1500 IU potency dissolved in 5 mL diluent each (administered in 10 mL diluent in total) in previously treated patients with severe hemophilia A (factor VIII level \< 1%).
Interventions
Participants will receive 3000 IU Advate using one 3000 IU potency vial dissolved in 5 mL diluent followed by two 1500 IU potency vials dissolved in 5 mL diluent each (administered in 10 mL diluent in total) or the alternate sequence
Sponsors
Baxalta now part of Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participant is 18 to 65 years old, at the time of screening * Participant has provided signed informed consent * Participant has severe hemophilia A, defined by a baseline FVIII level \< 1% of normal, as tested at screening at the central laboratory * Participant's weight is between 55-65 kg * Participant was previously treated with FVIII concentrate(s) for a minimum of 150 exposure days prior to study entry * If Participant is HIV positive, he must be immunocompetent as determined with a CD4 count ≥ 200 cells/mm³ (CD4 count at screening) * Participant is willing and able to comply with the requirements of the protocol
Exclusion criteria
* Participant has a detectable FVIII inhibitor at screening, with a titer ≥ 0.4 Bethesda unit (BU) (Nijmegen modification of the Bethesda Assay) measured at the central laboratory * Participant has a history of FVIII inhibitors with a titer ≥ 0.4 BU (by Nijmegen assay) or ≥ 0.5 BU (by Bethesda Assay) at any time prior to screening * Participant has undergone a surgery within 21 days prior to screening or within 6 weeks prior to the anticipated first pharmacokinetics(PK) infusion * Participant has an abnormal renal function (serum creatinine \> 1.5 mg/dL) * Participant has active hepatic disease (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels \>5 times the upper limit of normal) * Participant has severe chronic liver disease as evidenced by, but not limited to, any of the following: International Normalized Ratio (INR) \> 1.4, hypoalbuminemia, portal vein hypertension including presence of otherwise unexplained splenomegaly, and history of esophageal varices * Participant has clinical and/or laboratory evidence of abnormal hemostasis from causes other than hemophilia A (eg, late-stage chronic liver disease, immune thrombocytopenia purpura) * Participant is currently receiving, or is scheduled to receive during the course of the clinical study, an immunomodulating drug other than anti-retroviral chemotherapy (eg, alfa-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day) * Participant has a known hypersensitivity to mouse or hamster proteins * Participant has participated in another clinical study involving an investigational product or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an investigational product or investigational device during the course of this clinical study * Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures * Participant is a member of the team conducting this clinical study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, or parents) as well as employees of the investigator or site personnel conducting the clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). Chromogenic Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | Computed using the linear trapezoidal method. |
| Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). One-stage Activated Partial Thromboplastin Time (aPTT) Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | Computed using the linear trapezoidal method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incremental Recovery at Cmax - Chromogenic Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3 hours. | Determined as the highest Factor VIII (FVIII) activity achieved post-infusion |
| Incremental Recovery at Cmax - One-stage aPTT Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3 hours. | Determined as the highest FVIII activity achieved post-infusion |
| Incremental Recovery at 30 Minutes- Chromogenic Assay | 30 minutes pre-infusion and 30 minutes post-infusion | Change in factor VIII concentration from pre-infusion to 30 minutes post-infusion |
| Incremental Recovery at 30 Minutes- One-stage aPTT Assay | 30 minutes pre-infusion and 30 minutes post-infusion | Change in factor VIII concentration from pre-infusion to 30 minutes post-infusion |
| Elimination Phase Half-life- Chromogenic Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | calculated as log\_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model |
| Elimination Phase Half-life- One-stage aPTT Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | calculated as log\_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model |
| FVIII Clearance- Chromogenic Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | computed as the dose divided by total AUC |
| Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). Chromogenic Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | The total area under the plasma concentration versus time curve when the concentration is extrapolated to zero using the slope of the β-phase of the model. |
| Mean Residence Time (MRT)- Chromogenic Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | Computed as total area under the first moment curve (Total AUMC) divided by the total area under the concentration versus time curve (Total AUC) |
| Mean Residence Time (MRT)- One-stage aPTT Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | Computed as total area under the first moment curve (Total AUMC) divided by the total area under the concentration versus time curve (Total AUC) |
| Volume of Distribution at Steady State- Chromogenic Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | computed as Clearance (CL) \* Mean residence time (MRT) |
| Volume of Distribution at Steady State- One-stage aPTT Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | computed as CL \* MRT |
| Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- Chromogenic Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | Determined as the highest FVIII activity achieved post-infusion. |
| Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- One-stage aPTT Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | Determined as the highest FVIII activity achieved post-infusion. |
| FVIII Clearance- One-stage aPTT Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | Computed as the dose divided by total AUC |
| Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). One-stage aPTT Assay | Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours. | The total area under the plasma concentration versus time curve when the concentration is extrapolated to zero using the slope of the β-phase of the model. |
Countries
Bulgaria, Russia
Participant flow
Recruitment details
Enrollment was conducted in Russia and Bulgaria at 4 clinical sites.
Pre-assignment details
29 participants were enrolled. Six participants discontinued, (four were screen failures and two were withdrawn before randomization). Therefore 23 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants were randomized to receive via intravenous infusion 3000 International Units (IU) Advate using either one 3000 IU potency vial dissolved in 5 mL diluent followed by two 1500 IU potency vials dissolved in 5 mL diluent each (administered in 10 mL diluent in total) or the alternate sequence. | 23 |
| Total | 23 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 36.5 years STANDARD_DEVIATION 13.2 |
| Region of Enrollment Bulgaria | 14 Participants |
| Region of Enrollment Russian Federation | 9 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 0 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 23 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). Chromogenic Assay
Computed using the linear trapezoidal method.
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). Chromogenic Assay | 1158 (IU·h)/dL | Standard Deviation 335 |
| Two 1500 IU Vials | Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). Chromogenic Assay | 1264 (IU·h)/dL | Standard Deviation 364 |
p-value: 0.103paired t-test done on the Log(AUC 0-48h)
Primary
Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). One-stage Activated Partial Thromboplastin Time (aPTT) Assay
Computed using the linear trapezoidal method.
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). One-stage Activated Partial Thromboplastin Time (aPTT) Assay | 1129 (IU·h)/dL | Standard Deviation 310 |
| Two 1500 IU Vials | Area Under the Plasma Concentration Versus Time Curve From 0 to 48 Hours (AUC 0-48h). One-stage Activated Partial Thromboplastin Time (aPTT) Assay | 1226 (IU·h)/dL | Standard Deviation 358 |
p-value: 0.162paired t-test done on the Log(AUC 0-48h)
Secondary
Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). Chromogenic Assay
The total area under the plasma concentration versus time curve when the concentration is extrapolated to zero using the slope of the β-phase of the model.
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). Chromogenic Assay | 1267 (IU·h)/dL | Standard Deviation 395 |
| Two 1500 IU Vials | Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). Chromogenic Assay | 1383 (IU·h)/dL | Standard Deviation 437 |
Secondary
Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). One-stage aPTT Assay
The total area under the plasma concentration versus time curve when the concentration is extrapolated to zero using the slope of the β-phase of the model.
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). One-stage aPTT Assay | 1235 (IU·h)/dL | Standard Deviation 364 |
| Two 1500 IU Vials | Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity (AUC 0-infinity). One-stage aPTT Assay | 1348 (IU·h)/dL | Standard Deviation 427 |
Secondary
Elimination Phase Half-life- Chromogenic Assay
calculated as log\_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Elimination Phase Half-life- Chromogenic Assay | 13.27 hour | Standard Deviation 4.05 |
| Two 1500 IU Vials | Elimination Phase Half-life- Chromogenic Assay | 12.84 hour | Standard Deviation 4.31 |
Secondary
Elimination Phase Half-life- One-stage aPTT Assay
calculated as log\_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Elimination Phase Half-life- One-stage aPTT Assay | 13.80 hour | Standard Deviation 3.95 |
| Two 1500 IU Vials | Elimination Phase Half-life- One-stage aPTT Assay | 13.50 hour | Standard Deviation 2.81 |
Secondary
Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- Chromogenic Assay
Determined as the highest FVIII activity achieved post-infusion.
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- Chromogenic Assay | 94 IU/dL | Standard Deviation 21 |
| Two 1500 IU Vials | Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- Chromogenic Assay | 101 IU/dL | Standard Deviation 18 |
Secondary
Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- One-stage aPTT Assay
Determined as the highest FVIII activity achieved post-infusion.
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- One-stage aPTT Assay | 91 IU/dL | Standard Deviation 21 |
| Two 1500 IU Vials | Factor VIII (FVIII) Maximum Plasma Concentration (C-max)- One-stage aPTT Assay | 98 IU/dL | Standard Deviation 20 |
Secondary
FVIII Clearance- Chromogenic Assay
computed as the dose divided by total AUC
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | FVIII Clearance- Chromogenic Assay | 4.57 mL/(kg·h) | Standard Deviation 1.75 |
| Two 1500 IU Vials | FVIII Clearance- Chromogenic Assay | 3.99 mL/(kg·h) | Standard Deviation 1.53 |
Secondary
FVIII Clearance- One-stage aPTT Assay
Computed as the dose divided by total AUC
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | FVIII Clearance- One-stage aPTT Assay | 4.66 mL/(kg·h) | Standard Deviation 1.81 |
| Two 1500 IU Vials | FVIII Clearance- One-stage aPTT Assay | 4.06 mL/(kg·h) | Standard Deviation 1.46 |
Secondary
Incremental Recovery at 30 Minutes- Chromogenic Assay
Change in factor VIII concentration from pre-infusion to 30 minutes post-infusion
Time frame: 30 minutes pre-infusion and 30 minutes post-infusion
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Incremental Recovery at 30 Minutes- Chromogenic Assay | 1.62 (IU/dL)/(IU/kg) | Standard Deviation 0.42 |
| Two 1500 IU Vials | Incremental Recovery at 30 Minutes- Chromogenic Assay | 1.84 (IU/dL)/(IU/kg) | Standard Deviation 0.4 |
Secondary
Incremental Recovery at 30 Minutes- One-stage aPTT Assay
Change in factor VIII concentration from pre-infusion to 30 minutes post-infusion
Time frame: 30 minutes pre-infusion and 30 minutes post-infusion
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Incremental Recovery at 30 Minutes- One-stage aPTT Assay | 1.64 (IU/dL)/(IU/kg) | Standard Deviation 0.43 |
| Two 1500 IU Vials | Incremental Recovery at 30 Minutes- One-stage aPTT Assay | 1.90 (IU/dL)/(IU/kg) | Standard Deviation 0.32 |
Secondary
Incremental Recovery at Cmax - Chromogenic Assay
Determined as the highest Factor VIII (FVIII) activity achieved post-infusion
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Incremental Recovery at Cmax - Chromogenic Assay | 1.81 (IU/dL)/(IU/kg) | Standard Deviation 0.4 |
| Two 1500 IU Vials | Incremental Recovery at Cmax - Chromogenic Assay | 2.04 (IU/dL)/(IU/kg) | Standard Deviation 0.34 |
Secondary
Incremental Recovery at Cmax - One-stage aPTT Assay
Determined as the highest FVIII activity achieved post-infusion
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Incremental Recovery at Cmax - One-stage aPTT Assay | 1.75 (IU/dL)/(IU/kg) | Standard Deviation 0.43 |
| Two 1500 IU Vials | Incremental Recovery at Cmax - One-stage aPTT Assay | 1.96 (IU/dL)/(IU/kg) | Standard Deviation 0.32 |
Secondary
Mean Residence Time (MRT)- Chromogenic Assay
Computed as total area under the first moment curve (Total AUMC) divided by the total area under the concentration versus time curve (Total AUC)
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Mean Residence Time (MRT)- Chromogenic Assay | 17.02 hour | Standard Deviation 5.37 |
| Two 1500 IU Vials | Mean Residence Time (MRT)- Chromogenic Assay | 16.84 hour | Standard Deviation 5.81 |
Secondary
Mean Residence Time (MRT)- One-stage aPTT Assay
Computed as total area under the first moment curve (Total AUMC) divided by the total area under the concentration versus time curve (Total AUC)
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Mean Residence Time (MRT)- One-stage aPTT Assay | 16.95 hour | Standard Deviation 4.77 |
| Two 1500 IU Vials | Mean Residence Time (MRT)- One-stage aPTT Assay | 17.16 hour | Standard Deviation 4.65 |
Secondary
Volume of Distribution at Steady State- Chromogenic Assay
computed as Clearance (CL) \* Mean residence time (MRT)
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Volume of Distribution at Steady State- Chromogenic Assay | 0.72 dL/kg | Standard Deviation 0.23 |
| Two 1500 IU Vials | Volume of Distribution at Steady State- Chromogenic Assay | 0.61 dL/kg | Standard Deviation 0.13 |
Secondary
Volume of Distribution at Steady State- One-stage aPTT Assay
computed as CL \* MRT
Time frame: Within 30 minutes prior to the start of the infusion; and after the end of the infusion at 15, 30 minutes, and 1, 3, 6, 9, 24, 28, 32, and 48 hours.
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| One 3000 International Unit (IU) Vial | Volume of Distribution at Steady State- One-stage aPTT Assay | 0.74 dL/kg | Standard Deviation 0.19 |
| Two 1500 IU Vials | Volume of Distribution at Steady State- One-stage aPTT Assay | 0.64 dL/kg | Standard Deviation 0.11 |