Efficacy and Safety Study of a Recombinant Protein-Free Manufactured Factor VIII (rAHF-PFM) in Previously Untreated Hemophilia A Patients

• ClinicalTrials.gov Identifier: NCT00157157
• Recruitment Status: Completed
• First Posted: September 12, 2005
• Results First Posted: July 15, 2011
• Last Update Posted: May 24, 2021
• Sponsor: Baxalta now part of Shire
• Information provided by (Responsible Party): Takeda ( Baxalta now part of Shire )

Study Description

Brief Summary:

The purpose of this study is to evaluate whether Antihemophilic factor, recombinant, manufactured protein-free (rAHF-PFM) is effective and safe in the treatment of hemophilia A patients who have not been treated with factor VIII (FVIII) before.

Condition or disease	Intervention/treatment	Phase
Hemophilia A	Biological: Recombinant Antihemophilic Factor Manufactured and Formulated without Added Human or Animal Proteins (rAHF-PFM)	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 66 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Recombinant Antihemophilic Factor Manufactured and Formulated Without Added Human or Animal Proteins (rAHF-PFM): Evaluation of Immunogenicity, Efficacy, and Safety in Previously Untreated Patients With Hemophilia A
• Actual Study Start Date: April 1, 2004
• Actual Primary Completion Date: September 11, 2009
• Actual Study Completion Date: September 11, 2009

Arms and Interventions

Arm

Intervention/treatment

Experimental: Single Arm - All Participants; All subjects enrolled in the study who meet the eligibility criteria.

Biological: Recombinant Antihemophilic Factor Manufactured and Formulated without Added Human or Animal Proteins (rAHF-PFM); Treatment regimens were determined by the investigator, and may have been any combination of standard prophylaxis (25 to 50 IU/kg body weight, 3 to 4 times per week), investigator-determined prophylaxis, and/or on-demand treatment (dose selected by investigator). The treatment of bleeding episodes and perioperative management was at the discretion of the investigator and consistent with the institution's standard of care. For incremental recovery assessments, a single infusion at 50 +/- 5 IU/kg was to be given. Immune tolerance induction (ITI) therapy for subjects who developed factor VIII inhibitors was at the discretion of the investigator, based on the institution's guidelines or described in peer-reviewed literature, and was to be approved by the sponsor's medical director. rAHF-PFM was to be administered intravenously via bolus infusion, except for perioperative management when it may have been given either by continuous or bolus infusion.

Outcome Measures

Primary Outcome Measures :

1. Factor VIII Inhibitor Development [ Time Frame: Assessed during study period which was to be at least 75 exposure days or 3 years (whichever came first) ]
   Percentage of treated participants who developed factor VIII inhibitors

Secondary Outcome Measures :

1. Bleeding Episodes Treated With 1 to ≥4 Infusions [ Time Frame: Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) ]
   The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis
2. Assessment of Hemostasis for Treatment of Bleeding Episodes [ Time Frame: Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) ]
   Number of rAHF-PFM-treated bleeding episodes with treater assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within ~8 hrs of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within ~8 hrs after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within ~8 hrs after infusion. Requires >1 infusion for complete resolution; or None: No improvement or condition worsens.
3. Annualized Rate of Bleeding Episodes [ Time Frame: Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) ]
   Number of bleeding episodes per subject annualized over 1 year for all etiologies
4. Weekly rAHF-PFM Utilization [ Time Frame: Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) ]
   Weight-Adjusted Weekly Dose for Prophylaxis, On-Demand Treatment, and Perioperative Management. rAHF-PFM dose determined by the investigator (ie: standard regimen [25-50 IU/kg body weight, 3-4 times per week]; modified prophylactic regimen [dose and frequency selected by investigator] or on-demand treatment [dose selected by investigator]). Dosing to treat BEs was at investigator's discretion and in accordance with institution's standard of care. rAHF-PFM was administered I.V. via bolus infusion, except for perioperative management when it was given either by continuous or bolus infusion.
5. In Vivo Incremental Recovery [ Time Frame: 30 minutes pre-infusion to 30 minutes post-infusion ]
   Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits.
6. Assessment of Intra-operative Hemostasis [ Time Frame: Assessed at the time of discharge from recovery room ]
   Number of surgical procedures managed with rAHF-PFM and with surgeon's assessment of hemostasis based on a 4-point ordinal scale: Excellent: ≤ average predicted blood loss for matched procedures in healthy individuals Good: > average predicted blood loss, but ≤ maximal predicted blood loss for matched procedures in healthy individuals Fair: > maximal predicted blood loss for matched procedures in healthy individuals, and hemostasis was achieved None: uncontrolled hemostasis with proper dosing, necessitating a change in treatment regimen
7. Assessment of Postoperative Hemostasis [ Time Frame: Assessed at the time of discharge from hospital or clinic ]
   Number of surgical procedures managed with rAHF-PFM and with investigator's assessment of hemostasis based on a 4-point ordinal scale: Excellent: hemostasis was as good as or better than other licensed factor VIII products for matched procedure Good: hemostasis was probably as good as other licensed factor VIII products for matched procedure Fair: hemostasis was clearly < optimal for matched procedure, without need to change regimen None: bleeding from inadequate response with proper dosing, necessitating a change in regimen
8. Assessment of Blood Loss During Surgical Procedures [ Time Frame: Predicted volumes preoperatively estimated and actual volumes intraoperatively recorded ]
   Percentage of actual intraoperative blood loss compared to preoperatively predicted average and maximal blood loss in hemostatically normal matched individuals (from institutional blood bank records)
9. Adverse Events Deemed Related to Treatment [ Time Frame: Reported during the study period which was to be at least 75 exposure days or 3 years (whichever came first) ]
   Percentage of participants who reported AEs deemed related to treatment with rAHF-PFM
10. Development of Antibodies to Heterologous Proteins [ Time Frame: Assessed at baseline, throughout the duration of the study, which was to be at least 75 exposure days or 3 years (whichever came first), and at the termination visit. ]
    Percentage of treated participants who developed antibodies to heterologous proteins (ie, Chinese Hamster Ovary Cell Protein, Murine IgG, or Recombinant Human VWF)

Eligibility Criteria

• Ages Eligible for Study: up to 6 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• The subject has severe or moderately severe hemophilia A as defined by a baseline factor VIII level <= 2% of normal, as documented at screening
• The subject is < 6 years of age
• The subject's legally authorized representative has provided written informed consent

Exclusion Criteria:

• The subject has a history of exposure to factor VIII other than rAHF PFM or more than 3 infusions of commercially available rAHF PFM (i.e., ADVATE) within 28 days prior to screening, as determined by the subject's medical history. Any infusion of factor VIII replacement products prior to the 28-day period excludes the subject from participation
• The subject has received more than 3 infusions of rAHF PFM (commercially available and/or study product) between screening and prior to the initial recovery infusion
• The subject has a detectable inhibitor to factor VIII, as measured in the screening sample by the Nijmegen assay in the central laboratory
• The subject has a history of inhibitor to factor VIII at any time prior to screening
• The subject has a known hypersensitivity to rAHF PFM

• The subject has any 1 of the following laboratory abnormalities at the time of screening:

  1. Platelet count < 100,000/mm^3
  2. Hemoglobin concentration < 10 g/dL (100 g/L)
  3. Serum creatinine > 1.5 times the upper limit of normal (ULN) for age
  4. Total bilirubin > 2 times the ULN for age
• The subject has an inherited or acquired hemostatic defect other than hemophilia A (e.g., qualitative platelet defect or von Willebrand's disease)
• The subject is known to be seropositive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV), as determined by the subject's medical history
• At the time of enrollment, the subject has a clinically significant chronic disease other than hemophilia A
• The subject is currently participating in another investigational drug study, or has participated in any clinical study involving an investigational drug within 120 days of the screening visit
• The subject (or the subject's legally authorized representative) is identified by the investigator as being unable or unwilling to cooperate with study procedures
• The subject has received any blood product, including packed red blood cells (RBC), platelets, plasma, or cryoprecipitate

Contacts and Locations

Locations

United States, Arizona

Phoenix, Arizona, United States

United States, Arkansas

Little Rock, Arkansas, United States

United States, California

Los Angeles, California, United States

United States, District of Columbia

Washington, District of Columbia, United States

United States, Georgia

Atlanta, Georgia, United States

United States, Illinois

Chicago, Illinois, United States

Peoria, Illinois, United States

United States, Indiana

Indianapolis, Indiana, United States

United States, Iowa

Iowa City, Iowa, United States

United States, Louisiana

New Orleans, Louisiana, United States

United States, Michigan

Ann Arbor, Michigan, United States

Detroit, Michigan, United States

United States, Minnesota

Minneapolis, Minnesota, United States

United States, New York

New Hyde Park, New York, United States

New York, New York, United States

United States, Pennsylvania

Philadelphia, Pennsylvania, United States

United States, Texas

Houston, Texas, United States

Austria

Vienna, Austria

Canada, Ontario

Toronto, Ontario, Canada

France

Caen, France

Le Kremlin-Bicêtre, France

Lyon, France

Marseille, France

Nantes, France

Paris, France

Germany

Bremen, Germany

Frankfurt, Germany

Hannover, Germany

Münster, Germany

Italy

Milano, Italy

Puerto Rico

San Juan, Puerto Rico

Spain

Barcelona, Spain

Sweden

Stockholm, Sweden

United Kingdom

Cardiff, Wales, United Kingdom

London, United Kingdom

Sponsors and Collaborators

Baxalta now part of Shire

Investigators

• Study Director: Study Director; Takeda

More Information

Publications of Results:

Ewenstein B., Patrone L, Schroth P, Spotts G, Fritsch S, Pavlova B, Ehrlich H. Efficacy of antihemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM) in bleed prevention. J Thromb Haemost. 2007; 5(Suppl 2): P-S-179.

Ewenstein B., Patrone L, Schroth P, Spotts G, Fritsch S, Pavlova B, Ehrlich H. Efficacy of antihemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM) in bleed treatment. J Thromb Haemost. 2007; 5(Suppl 2)v: P-S-180.

Shapiro A, Gruppo R, Pabinger I, Collins PW, Hay CR, Schroth P, Casey K, Patrone L, Ehrlich H, Ewenstein BM. Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A. Expert Opin Biol Ther. 2009 Mar;9(3):273-83. doi: 10.1517/14712590902729392 .

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Auerswald G, Thompson AA, Recht M, Brown D, Liesner R, Guzmán-Becerra N, Dyck-Jones J, Ewenstein B, Abbuehl B. Experience of Advate rAHF-PFM in previously untreated patients and minimally treated patients with haemophilia A. Thromb Haemost. 2012 Jun;107(6):1072-82. doi: 10.1160/TH11-09-0642. Epub 2012 Apr 4.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT00157157
• Other Study ID Numbers: 060103; 2004-001623-38 ( EudraCT Number )
• First Posted: September 12, 2005
• Results First Posted: July 15, 2011
• Last Update Posted: May 24, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

Keywords provided by Takeda ( Baxalta now part of Shire ):

Factor VIII Deficiency

Additional relevant MeSH terms:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Factor VIII; Coagulants