Hemophilia A
Conditions
Brief summary
The purpose of this study is to determine the effect of 3 doses of ADVATE rAHF-PFM on initial recovery (% increase \[IU/dL\] per IU/kg infused) and major single-infusion pharmacokinetic parameters. The 3 doses are 15, 30, and 50 IU/kg. Prior to each infusion, subjects will not have received treatment with a factor VIII concentrate for at least 3 days. Blood samples will be drawn within 30 minutes pre-infusion and at 0.25, 0.5, 1, 3, 6, 9, 24, 28, 32 and 48 hours post-infusion. A washout period of at least 3 days, but no more than 30 days between the last blood draw and the next infusion will be observed. During participation, subjects will maintain their preexisting treatment regimens with ADVATE rAHF-PFM or other factor VIII concentrate. A secondary objective is to investigate the relationship between pharmacokinetic parameters at each dose level and the levels of von Willebrand factor ristocetin cofactor activity and von Willebrand factor antigen at baseline.
Interventions
15 IU/kg rAHF-PFM
Sponsors
Baxalta now part of Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* The subject has severe hemophilia A as defined by a baseline factor VIII activity \<1% of normal; tested at screening. (A minimum washout period of 3 days is required before the blood sample can be drawn to determine baseline factor VIII levels.) * The subject has a documented history of at least 150 exposure days to factor VIII concentrates (either plasma-derived or recombinant). * The subject is within 12 to 65 years of age. * The subject has a Karnofsky performance score \>60. * The subject is human immunodeficiency virus negative (HIV-) or HIV+ with CD4 count \>=400 cells/mm3 (CD4 count determined at screening, if necessary). * The subject or subject´s legally authorized representative has provided written informed consent.
Exclusion criteria
* The subject has a known hypersensitivity to mouse or hamster proteins or to factor VIII concentrates. * The subject has a history of factor VIII inhibitors with titer \>=0.8 BU (Bethesda Assay) or \>=0.4 BU (Nijmegen modification of the Bethesda Assay) any time prior to screening. * The subject has a detectable factor VIII inhibitor at screening, \>=0.4 BU (Nijmegen modification of the Bethesda Assay), in the Baxter central laboratory. * The subject 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. * The subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (e.g. qualitative platelet defect or von Willebrand´s Disease). * The subject has participated in another investigational study within 30 days of enrollment. * The subject´s clinical condition may require a major or moderate surgery (estimated blood loss \>500 mL) during the period of participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Initial Recovery | Pharmacokinetic evaluations: 30 minutes pre-infusion to 30 minutes post-infusion | Percent increase in factor VIII concentration per dose from pre- to post-infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve/Dose | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Area under the plasma factor VIII concentration versus time curve (AUC) estimated by linear trapezoidal method per dose. |
| Terminal Half-life | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Computed from the regression slope in the terminal phase of the model (the slope is biphasic). Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. |
| Total Area Under the Curve | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Total AUC with extrapolation using the slope of the β-phase |
| Total Area Under the Moment Curve | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Total area under the first moment curve (AUMC) estimated by linear trapezoidal methods |
| Weight-adjusted Clearance | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Computed as weight-adjusted dose divided by total AUC |
| Area Under the Curve | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve. |
| Volume of Distribution at Steady State | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Computed as weight-adjusted CL \* Mean Residence Time |
| Maximum Plasma Concentration | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Maximal factor VIII concentration after infusion |
| Pre-infusion Von Willebrand Factor Ristocetin Cofactor Activity (VWF:Rco) | At baseline and before each pharmacokinetic evaluation | Percentage of normal VWF:Rco activity. Normal is a lab standard consisting of a non-hemophilic population. Relationships between baseline VWF:Rco and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically. |
| Pre-infusion Von Willebrand Factor Antigen (VWF:Ag) | At baseline and before each pharmacokinetic evaluation | Percentage of VWF:Ag. Relationships between baseline VWF:Ag and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically. |
| Mean Residence Time | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Computed as total AUMC divided by total AUC |
Countries
United States
Participant flow
Recruitment details
Recruitment was conducted in the United States at 8 study sites.
Pre-assignment details
Participants were screened for a maximum of 30 days. Participants were randomized to a single sequence of the 3 doses of Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (rAHF-PFM). Before each pharmacokinetic evaluation, at least a 3 day washout period and negative factor VIII inhibitor titer was required.
Participants by arm
| Arm | Count |
|---|---|
| Treated Participants Participants who received at least 1 infusion of rAHF-PFM. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 3 | Lost to Follow-up | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Treated Participants |
|---|---|
| Age, Categorical <=18 years | 7 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants |
| Age, Continuous | 23.8 years STANDARD_DEVIATION 9.6 |
| Region of Enrollment United States | 26 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 26 |
| serious Total, serious adverse events | 0 / 26 |
Outcome results
Primary
Initial Recovery
Percent increase in factor VIII concentration per dose from pre- to post-infusion
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion to 30 minutes post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Initial Recovery | 1.7 IU/dL per IU/kg |
| Medium Dose | Initial Recovery | 1.6 IU/dL per IU/kg |
| High Dose | Initial Recovery | 1.8 IU/dL per IU/kg |
Comparison: Null Hypothesis: The mean log initial recovery will be the same in each dose group.p-value: 0.1662ANOVA
Secondary
Area Under the Curve
AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Area Under the Curve | 300.1 IU*hour/dL |
| Medium Dose | Area Under the Curve | 595.2 IU*hour/dL |
| High Dose | Area Under the Curve | 1055.8 IU*hour/dL |
Secondary
Area Under the Curve/Dose
Area under the plasma factor VIII concentration versus time curve (AUC) estimated by linear trapezoidal method per dose.
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Area Under the Curve/Dose | 21.2 IU*hour/dL per IU/kg |
| Medium Dose | Area Under the Curve/Dose | 20.5 IU*hour/dL per IU/kg |
| High Dose | Area Under the Curve/Dose | 22.3 IU*hour/dL per IU/kg |
Comparison: Null Hypothesis: The mean log AUC/dose will be the same in each dose group.p-value: 0.0965ANOVA
Secondary
Maximum Plasma Concentration
Maximal factor VIII concentration after infusion
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Maximum Plasma Concentration | 26.0 IU/dL |
| Medium Dose | Maximum Plasma Concentration | 50.0 IU/dL |
| High Dose | Maximum Plasma Concentration | 93.0 IU/dL |
Secondary
Mean Residence Time
Computed as total AUMC divided by total AUC
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Mean Residence Time | 14.6 hour |
| Medium Dose | Mean Residence Time | 12.8 hour |
| High Dose | Mean Residence Time | 14.7 hour |
Secondary
Pre-infusion Von Willebrand Factor Antigen (VWF:Ag)
Percentage of VWF:Ag. Relationships between baseline VWF:Ag and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically.
Time frame: At baseline and before each pharmacokinetic evaluation
Population: Intent to treat: participants who received at least 1 of the 3 infusions of rAHF-PFM and had pharmacokinetic evaluation(s).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Pre-infusion Von Willebrand Factor Antigen (VWF:Ag) | 103.0 U/dL |
| Medium Dose | Pre-infusion Von Willebrand Factor Antigen (VWF:Ag) | 117.0 U/dL |
| High Dose | Pre-infusion Von Willebrand Factor Antigen (VWF:Ag) | 109.5 U/dL |
Comparison: Regression analysis: relationship of initial recovery to pre-infusion level of VWF:Ag with dose groups combined.p-value: 0.3696Regression, Linear
Comparison: Regression analysis: relationship of AUC/Dose to pre-infusion level of VWF:Ag with dose groups combined.p-value: 0.0001Regression, Linear
Comparison: Regression analysis: relationship of terminal half-life to pre-infusion level of VWF:Ag with dose groups combined.p-value: <0.0001Regression, Linear
Secondary
Pre-infusion Von Willebrand Factor Ristocetin Cofactor Activity (VWF:Rco)
Percentage of normal VWF:Rco activity. Normal is a lab standard consisting of a non-hemophilic population. Relationships between baseline VWF:Rco and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically.
Time frame: At baseline and before each pharmacokinetic evaluation
Population: Intent to treat: participants who received at least 1 of the 3 infusions of rAHF-PFM and had pharmacokinetic evaluation(s)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Pre-infusion Von Willebrand Factor Ristocetin Cofactor Activity (VWF:Rco) | 83.0 Percent of normal VWF:Rco activity |
| Medium Dose | Pre-infusion Von Willebrand Factor Ristocetin Cofactor Activity (VWF:Rco) | 80.5 Percent of normal VWF:Rco activity |
| High Dose | Pre-infusion Von Willebrand Factor Ristocetin Cofactor Activity (VWF:Rco) | 80.5 Percent of normal VWF:Rco activity |
Comparison: Regression analysis: Relationship of initial recovery to pre-infusion level of VWF:Rco with dose groups combined.p-value: 0.7048Regression, Linear
Comparison: Regression analysis: relationship of AUC/Dose to pre-infusion level of VWF:Rco with dose groups combined.p-value: 0.0322Regression, Linear
Comparison: Regression analysis: relationship of terminal half-life to pre-infusion level of VWF:Rco with dose groups combined.p-value: 0.0056Regression, Linear
Secondary
Terminal Half-life
Computed from the regression slope in the terminal phase of the model (the slope is biphasic). Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Terminal Half-life | 11.3 hour |
| Medium Dose | Terminal Half-life | 12.3 hour |
| High Dose | Terminal Half-life | 11.2 hour |
Comparison: Null Hypothesis: The mean terminal half-life will be the same in each dose group.p-value: 0.5057ANOVA
Secondary
Total Area Under the Curve
Total AUC with extrapolation using the slope of the β-phase
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Total Area Under the Curve | 318.5 IU*hour/dL |
| Medium Dose | Total Area Under the Curve | 616.3 IU*hour/dL |
| High Dose | Total Area Under the Curve | 1116.0 IU*hour/dL |
Secondary
Total Area Under the Moment Curve
Total area under the first moment curve (AUMC) estimated by linear trapezoidal methods
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Total Area Under the Moment Curve | 4760.9 IU*hour^2/dL |
| Medium Dose | Total Area Under the Moment Curve | 7115.1 IU*hour^2/dL |
| High Dose | Total Area Under the Moment Curve | 16464.7 IU*hour^2/dL |
Secondary
Volume of Distribution at Steady State
Computed as weight-adjusted CL \* Mean Residence Time
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Volume of Distribution at Steady State | 0.7 dL/kg |
| Medium Dose | Volume of Distribution at Steady State | 0.6 dL/kg |
| High Dose | Volume of Distribution at Steady State | 0.6 dL/kg |
Secondary
Weight-adjusted Clearance
Computed as weight-adjusted dose divided by total AUC
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Per protocol population: participants who were randomized, received all 3 doses of rAHF-PFM, and had pharmacokinetic assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose | Weight-adjusted Clearance | 4.71 mL/kg*hour |
| Medium Dose | Weight-adjusted Clearance | 4.88 mL/kg*hour |
| High Dose | Weight-adjusted Clearance | 4.47 mL/kg*hour |