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Study of Modified Recombinant Factor VIII (OBI-1) in Subjects With Acquired Hemophilia A

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Baxalta US Inc.
ClinicalTrials.gov Identifier:
NCT01178294
First received: August 6, 2010
Last updated: November 17, 2015
Last verified: November 2015
  Purpose
This study is to test whether the study drug (OBI-1) is safe and effective for the treatment of serious bleeding episodes in people with acquired hemophilia A.

Condition Intervention Phase
Hemophilia A
Biological: OBI-1
Phase 2
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Efficacy and Safety of B-Domain Deleted Recombinant Porcine Factor VIII (OBI-1) in the Treatment of Acquired Hemophilia A Due to Factor VIII Inhibitory Auto-antibodies

Resource links provided by NLM:


Further study details as provided by Baxalta US Inc.:

Primary Outcome Measures:
  • Percentage of Serious Bleeding Episodes Responsive to OBI-1 [ Time Frame: 24 hours after initiation of treatment ] [ Designated as safety issue: No ]
    The initial serious ("qualifying") bleeding episode for each subject was analyzed for the primary efficacy outcome measure. A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'.


Secondary Outcome Measures:
  • Overall Percentage of Serious Bleeding Episodes Successfully Controlled With OBI-1 Therapy, as Assessed by the Investigator [ Time Frame: At the time of final treatment dosing (varied from participant to participant depending on bleeding episodes) ] [ Designated as safety issue: No ]
    Treatment success was defined as control of qualifying bleeding episode at the time of final treatment dosing. A serious bleeding episode was considered 'successfully controlled' if the investigator had checked 'completed OBI-1 therapy as treatment success' on the eCRF.

  • Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at Designated Assessment Time Points After the Initiation of Therapy, as Assessed by the Investigator [ Time Frame: 8 hours ] [ Designated as safety issue: No ]
    A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'.

  • Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at Designated Assessment Time Points After the Initiation of Therapy, as Assessed by the Investigator [ Time Frame: 16 hours ] [ Designated as safety issue: No ]
    A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'.

  • Frequency of Infusions of OBI-1 Required to Successfully Control Qualifying Bleeding Episodes [ Time Frame: Time of successful control of qualifying bleeding episode (varied from participant to participant) ] [ Designated as safety issue: No ]
    'Frequency of infusions' was calculated as the 'average number of infusions per day'. 'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'.

  • Total Dose of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes [ Time Frame: Time of successful control of qualifying bleeding episode (varied from participant to participant) ] [ Designated as safety issue: No ]
    'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'.

  • Total Number of Infusions of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes [ Time Frame: Time of successful control of qualifying bleeding episode (varied from participant to participant) ] [ Designated as safety issue: No ]
    'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'. A serious bleeding episode was considered 'successfully controlled' if the investigator had checked 'completed OBI-1 therapy as treatment success' on the eCRF.

  • Correlation Between Positive Response to OBI-1 Therapy at 8 Hours and Eventual Control of Serious Bleeding Episodes at 24 Hours [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
  • Correlation Between Response to OBI-1 Therapy at 16 Hours and Eventual Control of Serious Bleeding Episodes at 24 Hours [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
  • Correlation Between Response to OBI-1 Therapy at Specified Time Points and Eventual Control of Serious Bleeding Episodes at 24 Hours [ Time Frame: 24 hours ] [ Designated as safety issue: No ]
  • Correlation Between the Pre-infusion Anti-OBI-1 Antibody Titers, the Total Dose of OBI-1, the Outcome at 24 Hours and the Eventual Control of the Bleeding Episode [ Time Frame: Through 90 days ± 7 days following final OBI-1 dose ] [ Designated as safety issue: No ]
  • Pharmacokinetics (PK) Analysis- Plasma Clearance [ Time Frame: Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours ] [ Designated as safety issue: No ]
    Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics.

  • PK Analysis- Volume of Distribution (Vd) at Steady State [ Time Frame: Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours ] [ Designated as safety issue: No ]
    Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics.

  • PK Analysis- Area Under the Concentration-time Curve (AUC) From Time 0 to the Last Measurable Concentration [ Time Frame: Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours ] [ Designated as safety issue: No ]
    Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. AUC was calculated as area under the percent activity-time curve.

  • PK Analysis- Terminal Half-life [ Time Frame: Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours ] [ Designated as safety issue: No ]
    Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. Half-life was calculated as the time it took to reduce percent activity by half.

  • Number of Participants Who Developed de Novo Anti-OBI-1 Antibody Titers [ Time Frame: Through 90 days ± 7 days following final OBI-1 dose ] [ Designated as safety issue: Yes ]
  • Number of Participants Who Developed an Anti-host Cell Protein Baby Hamster Kidney (BHK) Antibody Titer [ Time Frame: Through 90 days ± 7 days following final OBI-1 dose ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • Anti-human Factor VIII Antibody Titer [ Time Frame: Through 90 days ± 7 days following final OBI-1 dose ] [ Designated as safety issue: Yes ]

Enrollment: 29
Study Start Date: November 2010
Study Completion Date: October 2013
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: OBI-1
Initial dose: 200 U/kg - additional doses at the discretion of the investigator based on FVIII activity level and clinical assessment of response to treatment (upper limit: 400 U/kg every 2 hours)
Biological: OBI-1
Intravenous infusion

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent from subject, trusted person or person who is legally authorized to sign on behalf of the participant (Legal Representative in U.S.), depending on local regulations
  • Participants with acquired hemophilia with autoimmune inhibitory antibodies to human factor VIII with a clinical diagnosis established by the following criteria: a) Prolonged activated partial thromboplastin time (aPTT), b) Prothrombin time (PT) ≤ upper limit of normal (ULN) + 2 seconds and platelet count within normal range, c) Abnormal aPTT mixing study (patient-normal control 1:1) consistent with a factor VIII inhibitors reduced factor VIII activity level (below 10%)
  • Has a serious bleeding episode, as documented by the investigator
  • Be willing and able to follow all instructions and attend all study visits
  • Participants taking anti-thrombotics (such as clopidogrel, heparin or heparin analogue) may be included provided three half-lives of the agent have elapsed since the last dose of the agent
  • Life expectancy, prior to onset of the hemorrhagic episode, of at least 90 days
  • Participants of reproductive age must use acceptable methods of contraception and if female, undergo pregnancy testing as part of the screening process

Exclusion Criteria:

  • Hemodynamically unstable after blood transfusion, fluid resuscitation and pharmacologic or volume replacement pressor therapy. This hemodynamic instability is characterized by symptomatic hypotension resulting in vital organ dysfunction, such as cardiac ischemia, oliguria (urine volume <0.5 mL/kg in the previous six hours), central nervous system hypoperfusion manifested by mental status change such as confusion (unless head injury or intracranial hemorrhage is present), pulmonary compromise, and/or acidosis (manifested by pH and lactate levels)
  • Has an established reason for bleeding that is not correctable
  • Bleeding episode assessed likely to resolve on its own if left untreated
  • Anti-OBI-1 inhibitor that exceeds 20 Bethesda Units (BU) (prospectively or retrospectively)
  • Subsequent bleeding episode at the site of the initial qualifying bleeding episode within two weeks following the final OBI-1 dose for the initial qualifying bleeding episode, or subsequent bleeding episode at a different site than the initial qualifying bleeding episode within 1 week following the final OBI-1 dose for the initial qualifying bleeding episode will not be considered "new" qualifying bleeding episodes
  • Prior history of bleeding disorder other than acquired hemophilia.
  • Known major sensitivity to therapeutic products of pig or hamster origin; examples include therapeutics of porcine origin (e.g. previously marketed porcine factor VIII, Hyate-C®) and recombinant therapeutics prepared from hamster cells (e.g. Humira®, Advate® and Enbrel®)
  • Use of hemophilia medication: rFVIIa within 3 hours prior to OBI-1 administration or aPCC treatment within 6 hours prior to OBI-1 administration
  • Participation in any other clinical study within 30 days of the first OBI-1 treatment
  • Anticipated need for treatment or device during the study that may interfere with the evaluation of the safety or efficacy of OBI-1, or whose safety or efficacy may be affected by OBI-1
  • Is currently pregnant, breastfeeding, or planning to become pregnant or father a child during the study
  • Abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject's safety or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study
  • Inability or unwillingness to comply with the study design, protocol requirements, or the follow-up procedures
  • Participant of majority age under legal protection
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01178294

Locations
United States, Indiana
Indiana Hemophilia and Thrombosis Center
Indianapolis, Indiana, United States, 46260
United States, Louisiana
Louisiana Center for Bleeding & Clotting Disorders
New Orleans, Louisiana, United States, 70112-2699
United States, Maryland
National Institutes of Health - Warren G. Magnuson Clinical Center
Bethesda, Maryland, United States, 20892-1508
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
United States, North Carolina
University of North Carolina at Chapel Hill Hospital
Chapel Hill, North Carolina, United States, 27599-7305
United States, Pennsylvania
The Pennsylvania State University and Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
United States, Tennessee
Vanderbilt University Medical Center, Hemostasis/Hemophilia Clinic
Nashville, Tennessee, United States, 37232-9830
Canada, Quebec
Maisonneuve-Rosemont Hospital
Montreal, Quebec, Canada, H1T 2M4
India
Apollo Hospitals
Chennai, Tamil Nadu, India, 600006
United Kingdom
Royal Free Hospital-Katharine Dormandy Haemophilia Centre and Thrombosis Unit
London, England, United Kingdom, NW3 2QG
Basingstoke and North Hampshire NHS Foundation Trust
Basingstoke, Hampshire/England, United Kingdom, RG249NA
Sponsors and Collaborators
Baxalta US Inc.
Investigators
Study Director: Heinrich Farin, MD Baxter Healthcare Corporation
  More Information

Responsible Party: Baxalta US Inc.
ClinicalTrials.gov Identifier: NCT01178294     History of Changes
Other Study ID Numbers: OBI-1-301 
Study First Received: August 6, 2010
Results First Received: April 28, 2015
Last Updated: November 17, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Baxalta US Inc.:
hemophilia A
haemophilia A
blood coagulation disorders
hemorrhagic disorders
coagulation protein disorder
hematologic diseases
Acquired Hemophilia A

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

ClinicalTrials.gov processed this record on September 30, 2016