Clinical trial NCT00243386: Prophylaxis Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A
Official title: Advate Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (ADVATE rAHF-PFM): A Phase 4 Study Comparing Two Prophylactic Regimens in Subjects With Severe or Moderately Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hemophilia A
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2005-10-24
Enrollment: 82
Sex: ALL
Minimum age (years): 7
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary purpose of this randomized, two-arm parallel clinical study in 66 previously treated patients with severe or moderately severe hemophilia A is to compare the rate of bleeding episodes for standard prophylaxis (20-40 IU/kg every 48 ± 6 hours; actual dose determined by the investigator) with that of alternate prophylaxis (20-80 IU/kg every 72 + 6 hours; actual dose determined by Baxter utilizing an algorithm and the patient's pharmacokinetic data). The rates of bleeding episodes for the on-demand regimen and the prophylaxis regimens will also be compared for the cross-over portion of the study. Enrolled patients will be treated originally on demand for a period of 6 months and then they will be randomized into one of the prophylaxis arms. Prophylactic treatment will last for a period of 12 months +/- 2 weeks.


Eligibility criteria: Inclusion Criteria:

* The subject has severe or moderately severe hemophilia A as defined by a baseline factor VIII level \<= 2% of normal, as tested at screening
* 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 7 to 65 years of age
* The subject has a Karnofsky performance score \> (greater than) 60
* The subject is human immunodeficiency virus negative (HIV-) or is HIV+ with a CD4 count \>= 400 cells/mm³ (CD4 count determined at screening, if necessary)
* The subject has been on a documented on-demand treatment regimen for at least 12 months immediately prior to enrollment
* The subject has a documented history (e.g. in medical charts or dispensing information, or signed investigator statement) of at least 8 joint hemorrhages in the 12 months immediately prior to enrollment
* The subject resides within the coverage area of the mobile compliance device; coverage area will be determined at screening
* The subject or the subject's legally authorized representative has provided written informed consent

Exclusion Criteria:

* The subject has a known hypersensitivity to factor VIII concentrates or mouse or hamster proteins
* The subject has a history of factor VIII inhibitors with a titer \>= 0.6 BU (by Bethesda or Nijmegen assay) at any time prior to screening
* The subject has a detectable factor VIII inhibitor at screening, with a titer \>= 0.4 BU (by Nijmegen Assay) in the 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 been treated during the last sixty (60) days prior to or is being treated at screening/enrollment with an immunomodulating drug.
* The subject has participated in another investigational study within thirty (30) days of enrollment
* The subject has previously participated in a clinical study with rAHF-PFM
* The subject's clinical condition may require a major surgery (defined as moderate to critical risk and perioperative blood loss ≥ 500 mL) during the period of the subject's participation in the study
* The subject is female of childbearing potential with a positive pregnancy test

Primary outcomes:
measure: Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens
timeFrame: 12 months ±2 weeks
measure: Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens
timeFrame: 12 months ±2 weeks
Secondary outcomes:
measure: Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Standard Prophylaxis Treatment Regimens
timeFrame: On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)
measure: Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and PK-Driven Prophylaxis Treatment Regimens
timeFrame: On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)
measure: Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Any Prophylaxis Treatment Regimens
timeFrame: On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
measure: Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm
timeFrame: 12 months ±2 weeks
measure: Bleeding Episodes Treated With 1 to ≥4 Infusions
timeFrame: Throughout the study period (4 years and 5 months)
measure: Assessment of Hemostasis for Treatment of Bleeding Episodes
timeFrame: On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
measure: Total Area Under the Curve (AUC)
timeFrame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
measure: Area Under the Curve
timeFrame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
measure: Maximum Plasma Concentration (C-max)
timeFrame: Within 1 hour post-infusion
measure: Adjusted Incremental Recovery (IR)
timeFrame: 30 minutes pre-infusion to 48 hours post-infusion
measure: Terminal Half-life
timeFrame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
measure: Weight-Adjusted Clearance
timeFrame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
measure: Mean Residence Time
timeFrame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
measure: Volume of Distribution at Steady State
timeFrame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
measure: Factor VIII Inhibitor Development
timeFrame: Throughout study period (4 years and 5 months)
measure: Number of Participants With AEs Related to Investigational Product (IP)
timeFrame: Throughout study period (4 years and 5 months)
measure: Number of Participants Who Reported ≥1 AE Regardless of Relatedness to Investigational Product (IP)
timeFrame: Throughout study period (4 years and 5 months)
measure: Number of Participants Who Reported ≥1 AE Regardless of Relatedness to IP by Treatment Regimen
timeFrame: Throughout the study period (4 years and 5 months)
measure: Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen
timeFrame: Throughout the study period (4 years and 5 months)
measure: AEs With Onset ≤1 Hour Following the End of an Infusion, Regardless of Relatedness
timeFrame: Throughout study period (4 years and 5 months)
measure: Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen
timeFrame: Throughout the study period (4 years and 5 months)
measure: Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS
timeFrame: Baseline
measure: Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens
timeFrame: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
measure: HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period
timeFrame: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
measure: Bodily Pain HRQoL Scores Change From On-Demand Period Through Prophylaxis Period
timeFrame: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
measure: Physical Component Scores (PCS) HRQoL Scores Change From On-Demand Period Through Prophylaxis Period
timeFrame: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
Other outcomes:
Locations:
city: Los Angeles
country: United States
state: California
city: Chicago
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: Minneapolis
country: United States
state: Minnesota
city: New York
country: United States
state: New York
city: Oklahoma City
country: United States
state: Oklahoma
city: Portland
country: United States
state: Oregon
city: Hershey
country: United States
state: Pennsylvania
city: Seattle
country: United States
state: Washington
city: Vienna
country: Austria
city: Brno
country: Czechia
city: Prague
country: Czechia
city: Athens
country: Greece
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Pecs
country: Hungary
city: Szeged
country: Hungary
city: Szombathely
country: Hungary
city: Florence
country: Italy
city: Milano
country: Italy
city: Gdansk
country: Poland
city: Krakow
country: Poland
city: Lublin
country: Poland
city: Warsaw
country: Poland
city: Wroclaw
country: Poland
city: Moscow
country: Russian Federation
city: Ljubljana
country: Slovenia
city: Cardiff
country: United Kingdom
city: Nottingham
country: United Kingdom
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Valentino LA, Mamonov V, Hellmann A, Quon DV, Chybicka A, Schroth P, Patrone L, Wong WY; Prophylaxis Study Group. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost. 2012 Mar;10(3):359-67. doi: 10.1111/j.1538-7836.2011.04611.x.