Trial Outcomes & Findings for Dose-Response Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A (NCT NCT00289536)

NCT ID: NCT00289536

Last Updated: 2021-06-10

Results Overview

Percent increase in factor VIII concentration per dose from pre- to post-infusion

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

38 participants

Primary outcome timeframe

Pharmacokinetic evaluations: 30 minutes pre-infusion to 30 minutes post-infusion

Results posted on

2021-06-10

Participant Flow

Recruitment was conducted in the United States at 8 study sites.

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.

Participant milestones

Participant milestones
Measure	Low Dose 15 IU/kg rAHF-PFM	Medium Dose 30 IU/kg rAHF-PFM	High Dose 50 IU/kg rAHF-PFM
Period 1 STARTED	9	8	9
Period 1 COMPLETED	9	8	9
Period 1 NOT COMPLETED	0	0	0
Period 2 STARTED	10	9	7
Period 2 COMPLETED	10	9	7
Period 2 NOT COMPLETED	0	0	0
Period 3 STARTED	7	9	10
Period 3 COMPLETED	7	9	9
Period 3 NOT COMPLETED	0	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Low Dose 15 IU/kg rAHF-PFM	Medium Dose 30 IU/kg rAHF-PFM	High Dose 50 IU/kg rAHF-PFM
Period 3 Lost to Follow-up	0	0	1

Baseline Characteristics

Dose-Response Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treated Participants n=26 Participants Participants who received at least 1 infusion of rAHF-PFM.
Age, Categorical <=18 years	7 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	19 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	23.8 years STANDARD_DEVIATION 9.6 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	26 Participants n=5 Participants
Region of Enrollment United States	26 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Percent increase in factor VIII concentration per dose from pre- to post-infusion

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Initial Recovery	1.7 IU/dL per IU/kg Interval 0.5 to 2.7	1.6 IU/dL per IU/kg Interval 0.4 to 2.6	1.8 IU/dL per IU/kg Interval 1.2 to 2.8

SECONDARY outcome

Timeframe: 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.

Area under the plasma factor VIII concentration versus time curve (AUC) estimated by linear trapezoidal method per dose.

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Area Under the Curve/Dose	21.2 IU*hour/dL per IU/kg Interval 8.8 to 43.3	20.5 IU*hour/dL per IU/kg Interval 6.5 to 42.2	22.3 IU*hour/dL per IU/kg Interval 14.5 to 46.9

SECONDARY outcome

Timeframe: 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.

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%.

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Terminal Half-life	11.3 hour Interval 5.4 to 19.9	12.3 hour Interval 6.0 to 20.0	11.2 hour Interval 7.5 to 25.1

SECONDARY outcome

Timeframe: 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.

AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Area Under the Curve	300.1 IU*hour/dL Interval 124.5 to 544.9	595.2 IU*hour/dL Interval 167.8 to 1104.8	1055.8 IU*hour/dL Interval 712.1 to 1778.3

SECONDARY outcome

Timeframe: 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.

Total AUC with extrapolation using the slope of the β-phase

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Total Area Under the Curve	318.5 IU*hour/dL Interval 131.8 to 648.8	616.3 IU*hour/dL Interval 194.4 to 1264.8	1116.0 IU*hour/dL Interval 723.3 to 2344.9

SECONDARY outcome

Timeframe: 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.

Total area under the first moment curve (AUMC) estimated by linear trapezoidal methods

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Total Area Under the Moment Curve	4760.9 IU*hour^2/dL Interval 1042.9 to 16315.9	7115.1 IU*hour^2/dL Interval 2673.6 to 28374.2	16464.7 IU*hour^2/dL Interval 7111.4 to 77439.7

SECONDARY outcome

Timeframe: 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.

Computed as weight-adjusted dose divided by total AUC

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Weight-adjusted Clearance	4.71 mL/kg*hour Interval 2.34 to 11.38	4.88 mL/kg*hour Interval 2.37 to 15.43	4.47 mL/kg*hour Interval 2.13 to 6.91

SECONDARY outcome

Timeframe: 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.

Computed as total AUMC divided by total AUC

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Mean Residence Time	14.6 hour Interval 7.2 to 25.1	12.8 hour Interval 7.5 to 24.7	14.7 hour Interval 9.2 to 33.0

SECONDARY outcome

Timeframe: 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.

Computed as weight-adjusted CL \* Mean Residence Time

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Volume of Distribution at Steady State	0.7 dL/kg Interval 0.4 to 0.9	0.6 dL/kg Interval 0.4 to 3.4	0.6 dL/kg Interval 0.3 to 0.8

SECONDARY outcome

Timeframe: 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.

Maximal factor VIII concentration after infusion

Outcome measures

Outcome measures
Measure	Low Dose n=23 Participants 15 IU/kg rAHF-PFM	Medium Dose n=23 Participants 30 IU/kg rAHF-PFM	High Dose n=23 Participants 50 IU/kg rAHF-PFM
Maximum Plasma Concentration	26.0 IU/dL Interval 13.0 to 42.0	50.0 IU/dL Interval 14.0 to 79.0	93.0 IU/dL Interval 65.0 to 143.0

SECONDARY outcome

Timeframe: 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)

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.

Outcome measures

Outcome measures
Measure	Low Dose n=26 Participants 15 IU/kg rAHF-PFM	Medium Dose n=26 Participants 30 IU/kg rAHF-PFM	High Dose n=26 Participants 50 IU/kg rAHF-PFM
Pre-infusion Von Willebrand Factor Ristocetin Cofactor Activity (VWF:Rco)	83.0 Percent of normal VWF:Rco activity Interval 40.0 to 152.0	80.5 Percent of normal VWF:Rco activity Interval 49.0 to 186.0	80.5 Percent of normal VWF:Rco activity Interval 33.0 to 182.0

SECONDARY outcome

Timeframe: 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).

Percentage of VWF:Ag. Relationships between baseline VWF:Ag and pharmacokinetic parameters (initial recovery, total AUC/dose, and half-life) were evaluated statistically.

Outcome measures

Outcome measures
Measure	Low Dose n=25 Participants 15 IU/kg rAHF-PFM	Medium Dose n=26 Participants 30 IU/kg rAHF-PFM	High Dose n=26 Participants 50 IU/kg rAHF-PFM
Pre-infusion Von Willebrand Factor Antigen (VWF:Ag)	103.0 U/dL Interval 57.0 to 307.0	117.0 U/dL Interval 63.0 to 309.0	109.5 U/dL Interval 61.0 to 329.0

Adverse Events

Safety Population (26 Participants)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Safety Population (26 Participants) n=26 participants at risk Participants who received at least 1 infusion of rAHF-PFM
Nervous system disorders Headache	11.5% 3/26 • Number of events 3 • 15 months AEs were collected by the investigators at study visits, and may result from laboratory and vital sign assessments collected or measured at the study visits
Musculoskeletal and connective tissue disorders Pain in extremity	7.7% 2/26 • Number of events 2 • 15 months AEs were collected by the investigators at study visits, and may result from laboratory and vital sign assessments collected or measured at the study visits

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Baxter's agreements with PIs vary per individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication or 1 year after study completion. Baxter requires a review of results communications (e.g., for confidential information) ≥45 days prior to submission or communication. Baxter may request an additional delay of up to 60 days (e.g., to allow for intellectual property protection).
Publication restrictions are in place

Restriction type: OTHER