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Efficacy and Safety Study of Prophylactic Versus On-Demand Treatment With Feiba NF in Subjects With Hemophilia A or B and a High Titer Inhibitor

Primary Purpose

Hemophilia A or B With Inhibitors, Hemophilia A, Hemophilia B

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Factor VIII Inhibitor Bypassing Activity (nanofiltered, vapor heat-treated)
Factor VIII Inhibitor Bypassing Activity (nanofiltered, vapor heat-treated)
Sponsored by
Baxalta now part of Shire
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia A or B With Inhibitors focused on measuring Hemophilia A, Factor VIII Inhibitor, Factor IX Inhibitor, Hemophilia B

Eligibility Criteria

4 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Signed and dated informed consent form by the participant or the participant's legally authorized representative
  • The participant is ≥ 4 to ≤ 65 years of age
  • The participant has a Karnofsky performance score of ≥ 60
  • Hemophilia A and B of any severity, with documented history of high-titer inhibitor (> 5 Bethesda unit (BU)) for at least 12 months; or, if inhibitor titer is ≤ 5 BU, and the participant is refractory with increased dosing of either factor VIII (FVIII) or factor IX (FIX), as demonstrated from the participant's medical history
  • Currently being treated on an on-demand basis for treatment of bleeding episodes
  • Adequate venous access, with or without central venous device
  • ≥ 12 bleeding episodes requiring treatment with by-passing agents in the past 12 months, based on medical history
  • Competent in-home treatment and infusion therapy
  • Currently using bypassing agents (activated prothrombin complex concentrate (APCC) or recombinant activated factor VII (rFVIIa)) for treatment of bleeding episodes
  • HCV-, either by antibody testing or polymerase chain reaction (PCR); or HCV+ with stable hepatic disease
  • HIV-, or HIV+ with stable disease and CD4 count > 200 cells/mm3 at screening
  • Female participant of childbearing potential, presents with a negative serum pregnancy test, and agrees to employ adequate birth control measures for the duration of the study

Exclusion Criteria:

  • Currently receiving immune tolerance induction (ITI)
  • Currently on regular prophylactic therapy to prevent bleeding episodes
  • Clinically symptomatic liver disease (e.g. diagnosis of cirrhosis [confirmed by liver biopsy], portal vein hypertension, ascites, prothrombin time (PT) 5 seconds above upper limit of normal)
  • Platelet count < 100,000/ml
  • Planned elective surgery during participation in this study
  • Participant is currently participating in another clinical study and has received an investigational product or device within 30 days prior to study entry
  • Planned use of pegylated or non-pegylated alpha-interferon with or without ribavirin for HCV infected participants or planned use of a protease inhibitor for HIV infected participants. Participants currently taking any of these medications for a 30-day course are eligible.
  • Clinically significant increase in D-dimer levels from historical baseline and/or associated with chronic liver disease or clinically evident thromboembolic event
  • Known hypersensitivity to anti-inhibitor coagulant complexes (AICCs)
  • Currently treated with a systemic immunomodulating drug
  • Prior history of thromboembolic event: acute myocardial infarction, deep vein thrombosis, or pulmonary embolism
  • Diagnosis of advanced atherosclerosis, malignancy and/or other diseases that may increase the participant's risk of thromboembolic complications
  • Clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Prophylaxis arm

On-demand arm

Arm Description

Outcomes

Primary Outcome Measures

Reduction in Annualized Bleeding Episode Rate (ABR) Among Participants Receiving Prophylactic Treatment as Compared to Those Treated On-demand
Participants were Randomized to Receive 1 of the 2 Following Treatment Regimens: 1.On-Demand: FEIBA NF dose & dosing interval as prescribed by treating physician 2.Prophylaxis: 85 ± 15 U/kg of FEIBA NF every other day during 12-month prophylactic period Annualized rate of bleeding episodes was calculated as: (Number of bleeding episodes/observed treatment period in days) * 365.25

Secondary Outcome Measures

Annualized Bleeding Rate by Treatment Regimen, Bleeding Etiology, and Bleed Type
Spontaneous includes unknown/undermined etiology
Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens by Bleeding Etiology, and Bleeding Type
Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the t-test. The difference in mean transformed ABRs was used to perform statistical tests and generate p-values at a significance level of 5% Participants were Randomized to Receive 1 of the 2 Following Treatment Regimens: 1.On-Demand: FEIBA NF dose & dosing interval as prescribed by treating physician 2.Prophylaxis: 85 ± 15 U/kg of FEIBA NF every other day during 12-month prophylactic period
Annualized Bleeding Rate for New Target Joints
Target joints are ≥4 bleeds/6 months in any one of the following joints: ankles, knees, elbows, and hips; a target joint bleeding episode refers to an individual anatomical location.
Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens: New Target Joints
Annualized bleed rates (ABRs) were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using a two-sample, two-sided t-test. The difference in mean transformed ABRs was used to perform statistical tests and generate p-values at a significance level of 5%
Number of New Target Joints
Target Joints are defined as ≥4 bleeds/6 months in any one of the following joints: ankles, knees, elbows and hips
Assessment of Objective Clinical Symptoms- Visual Analog Scale (VAS): Pain in Adolescents and Adults (≥12 Years Old)
Pain caused by a bleeding episode in adolescents and adults (≥12 years old) was measured at pre-infusion (pre-inf) and at 6 ± 0.5 hours (h) and 24 ± 1 h post-infusion (post-inf) (after the last infusion given to treat a bleeding episode) on the VAS pain scale in millimeters from 0 (no pain) to 100 (worst possible pain). For analysis purposes, if short acting analgesics (duration of activity approximately 6 ± 0.5 h) were used, pain was assigned the highest possible score (100). Pain assessment occurred after each infusion related to single bleeding episodes. In case participants required an additional infusion within 24h, pain was assessed 6 ± 0.5 h and 24 ±1 h following the subsequent infusion. Change in VAS scores at 6 ± 0.5 h and 24 ±1 h post-infusion were also compared relative to pre-infusion VAS scores (ie, (pre-infusion VAS score) - (post-infusion VAS score)).
Assessment of Clinical Symptoms - Visual Analog Scale (VAS): Pain in Pediatrics (<12 Years Old)
Pain caused by a bleeding episode (BE) in pediatric participants (<12 years old) was measured at pre-infusion (pre-inf) and at 6 ± 0.5 h and 24 ± 1 h post-infusion (post-inf) (after the last infusion given to treat a bleeding episode) using the children's VAS pain scale (a facial expression scale with one end marked as no pain and the opposite end marked as the worst possible pain). For analysis purposes, if short acting analgesics (duration of activity approximately 6 ± 0.5 h) were used, pain was assigned the highest possible score (worst possible pain). Scores on the children's VAS scale are presented as: -No Pain -Mild Pain -Moderate pain -Severe pain -Very severe pain
Assessment of Clinical Symptoms - Range of Motion (ROM)
ROM was measured using a goniometer for 3 key joints (ie, ankles, knees, and elbows) at screening, month 6, and termination (end of study visit)
Assessment of Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 6 Hours
Number of rAHF-PFM-treated bleeding episodes with an assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within ~6 hours of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within ~6 hours after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within ~6 hours after infusion. Requires >1 infusion for complete resolution; None: No improvement or condition worsens
Assessment of Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 24 Hours
Number of rAHF-PFM-treated bleeding episodes with an assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within ~24 hours of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within ~24 hours after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within ~24 hours after infusion. Requires >1 infusion for complete resolution; None: No improvement or condition worsens
Total Weight Adjusted Dose to Control a Bleeding Episode
The Number of Bleeding Episode (BE) Which Required 1, 2, 3, or ≥4 Infusions to Control Bleeding
Abnormal Activated Partial Thromboplastin Time (aPTT) Assay Results
The normal reference range of values for aPTT is 22.8 - 31 seconds.
Abnormal D-Dimer Assay Results
The normal reference range of values for D-dimers is <500 ng/mL.
Abnormal Fibrinogen Assay Results
The normal reference range of values for fibrinogen is 200-400 mg/dL.
Abnormal Fibrin Degradation Products (FDP) Assay Results
The normal reference range of values for FDP is 0-5 ug/mL.
Abnormal Prothrombin Fragment F 1.2 Assay Results
The normal reference range of values for prothrombin fragment F 1.2 is 69-229 pmol/L.
Abnormal Prothrombin Time Assay Results
The normal reference range of values for PT is 9.7-12.3 sec.
Abnormal Thrombin-Antithrombin III (TAT) Assay Results
The normal reference range of values for TAT is 1-4.1 ug/L.
Viral Serology From Screening Visit and Study Termination Visit: Hepatitis A, Hepatitis B, and Hepatitis C
-Hepatitis A Virus Antibody (HAV Ab) -Hepatitis B Virus Core Antibody (HBcAb) -Hepatitis B Virus Surface Antibody (HBsAb) -Hepatitis B Virus Surface Antigen (HBsAg) -Hepatitis C Virus (HCV)
Viral Serology From Screening Visit and Study Termination Visit: HIV-1/2 Antibody (Ab)
Viral Serology From Screening Visit and Study Termination Visit: Parvovirus B19 IgG Antibody [IV]
Normal range (0 - 0.89 IV); High (> 0.89 IV) - Parvovirus B19 IgG Antibody [IV] (Parvo IgG Ab)
Viral Serology From Screening Visit and Study Termination Visit: Parvovirus B19 IgM Antibody [IV]
Normal range (0 - 0.89 IV); High (> 0.89 IV) - Parvovirus B19 IgM Antibody [IV] (Parvo IgM Ab)
Rate of Related Adverse Events (AEs) Per Year
Rate of Related Adverse Events (AEs) During or Within 1 Hour of Infusion Per Year
Number of Related Thromboembolic Adverse Events (AEs)
Absolute Changes in Inhibitor Titer of Hemophilia A Participants With Shifts in Factor VIII (FVIII) Inhibitor Titer Levels
Absolute Changes in Inhibitor Titer (or no change in low or high titer status): -Inhibitor Titer went from Low (≤5 BU) to Low (≤5 BU) -Inhibitor Titer went from Low (≤5 BU) to High (>5 BU) -Inhibitor Titer went from High (>5 BU) to Low (≤5 BU) -Inhibitor Titer went from High (>5 BU) to High (>5 BU)
Absolute Changes in Inhibitor Titer of Hemophilia B Participants With Shifts in Factor IX (FIX) Inhibitor Titer Levels
Absolute Changes in Inhibitor Titer (or no change in low or high titer status): -Inhibitor Titer went from Low (≤5 BU) to Low (≤5 BU) -Inhibitor Titer went from Low (≤5 BU) to High (>5 BU) -Inhibitor Titer went from High (>5 BU) to Low (≤5 BU) -Inhibitor Titer went from High (>5 BU) to High (>5 BU)
Pharmacoeconomics: Annual Days Lost Due to Bleeding (Work or School)
Pharmacoeconomics: Annual Number of Hospitalizations for Bleeding
Pharmacoeconomics: Annual Number of Hospitalizations for Indwelling Line
Pharmacoeconomics: Annual Number of Emergency Room Visits
Pharmacoeconomics: Annual Number of Physician's Office Visits
Pharmacoeconomics: Annual Total Length of Hospitalization for Bleeding
Pharmacoeconomics: Annual Total Length of Hospitalization for Indwelling Line
Pharmacoeconomics: Annual Total Number of Days Lost (Work or School)
Health-Related Quality of Life (HRQoL): EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) Index Scores
EQ-5D is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome. EQ-5D Index scores based on EQ-5D questionnaire were calculated for participants ≥14 years of age, at screening, 6 months, and at termination visit. Changes in scores at 6 months and termination were also calculated. A relatively higher score represents better quality of life.
Hemophilia-specific Quality of Life Questionnaire for Adults (Haem-A-QoL) ≥ 16 Years Old
The Haem-A-QoL instrument has been developed and used in Hemophilia A patients. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: Physical Health (PH), Sports & Leisure (S&L), School & Work (W&S), Dealing with Hemophilia (Dealing), Family Planning (FP), Feeling, Relationships (R'ships), Treatment, View, and Outlook for the Future (Future). A Haem-A-QoL Total Score (Total) was also calculated. For the Haem-A-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. Haem-A-QoL scores at screening, 6 months, and at termination visit were collected. Changes in scores at 6 months and termination were also calculated.
Hemophilia-specific Quality of Life Questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Parent's Evaluation
The Haemo-QoL is a quality of life (QoL) assessment instrument for children and adolescents with haemophilia. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: Physical Health (PH), Sports & School (S&S), Dealing with Hemophilia (Dealing), Family, Feeling, Relationships (R'ships), Treatment, View, Outlook for the Future (Future), Friends, Others, and Support. A Haemo-QoL Total Score (Total) was also calculated. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. Haemo-QoL scores at screening, 6 months, and at termination visit were collected. Changes in scores at 6 months and termination were also calculated.
Hemophilia-specific Quality of Life Questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Child's Evaluation
The Haemo-QoL is a quality of life (QoL) assessment instrument for children and adolescents with haemophilia. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: Physical Health (PH), Sports & School (S&S), Dealing with Hemophilia (Dealing), Family, Feeling, Relationships (R'ships), Treatment, View, Outlook for the Future (Future), Friends, Others, and Support. A Haemo-QoL Total Score (Total) was also calculated. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. Haemo-QoL scores at screening, 6 months, and at termination visit were collected. Changes in scores at 6 months and termination were also calculated.
Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Adults and Adolescents ≥12 Years Old
General pain was assessed using a VAS pain scale at screening, 6 months, and at termination. Unlike the VAS pain assessment for pain of bleeding episodes (Outcome above), this general pain assessment did not take use of analgesics into account. For the pain scale, a higher number indicates worse pain. The visual analog scale ranges from 0 to 100 where the endpoints are labeled 'Worst imaginable health state' (=0) and 'Best imaginable health state' (=100). A positive change from baseline indicates improvement. Change in VAS scores at 6 months and study termination were also compared relative to Baseline/Screening scores (ie, (Baseline/Screening VAS score) - (VAS score at 6 months and study termination).
Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Pediatrics <12 Years Old
General pain was assessed using the children's VAS pain scale (a facial expression scale with one end marked as no pain and the opposite end marked as the worst possible pain). Assessments were done at the screening, 6 months, and termination visits. Scores on the children's VAS scale are presented as: -No Pain -Mild Pain -Moderate pain -Severe pain -Very severe pain Unlike the VAS pain assessment for pain of bleeding episodes (Outcome above), this general pain assessment did not take use of analgesics into account. Change in VAS scores at 6 months and study termination were also compared relative to Baseline/Screening scores (ie, (Baseline/Screening VAS score) - (VAS score at 6 months and study termination).

Full Information

First Posted
February 25, 2009
Last Updated
April 29, 2021
Sponsor
Baxalta now part of Shire
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1. Study Identification

Unique Protocol Identification Number
NCT00851721
Brief Title
Efficacy and Safety Study of Prophylactic Versus On-Demand Treatment With Feiba NF in Subjects With Hemophilia A or B and a High Titer Inhibitor
Official Title
FEIBA NF: A Prospective, Open-label, Randomized, Parallel Study to Evaluate the Efficacy and Safety of Prophylactic Versus On-Demand Treatment in Subjects With Hemophilia A or B and a High Titer Inhibitor
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
March 31, 2009 (Actual)
Primary Completion Date
October 17, 2012 (Actual)
Study Completion Date
October 17, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Baxalta now part of Shire

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of the study was to determine the efficacy, safety, and health-related quality of life benefits with FEIBA NF prophylactic treatment as compared with on-demand treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia A or B With Inhibitors, Hemophilia A, Hemophilia B
Keywords
Hemophilia A, Factor VIII Inhibitor, Factor IX Inhibitor, Hemophilia B

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
52 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Prophylaxis arm
Arm Type
Experimental
Arm Title
On-demand arm
Arm Type
Active Comparator
Intervention Type
Biological
Intervention Name(s)
Factor VIII Inhibitor Bypassing Activity (nanofiltered, vapor heat-treated)
Other Intervention Name(s)
FEIBA NF
Intervention Description
85 ± 15 U/kg of FEIBA NF every other day during the 12-month prophylactic period
Intervention Type
Biological
Intervention Name(s)
Factor VIII Inhibitor Bypassing Activity (nanofiltered, vapor heat-treated)
Other Intervention Name(s)
FEIBA NF
Intervention Description
FEIBA NF dose and dosing interval as prescribed by the treating physician
Primary Outcome Measure Information:
Title
Reduction in Annualized Bleeding Episode Rate (ABR) Among Participants Receiving Prophylactic Treatment as Compared to Those Treated On-demand
Description
Participants were Randomized to Receive 1 of the 2 Following Treatment Regimens: 1.On-Demand: FEIBA NF dose & dosing interval as prescribed by treating physician 2.Prophylaxis: 85 ± 15 U/kg of FEIBA NF every other day during 12-month prophylactic period Annualized rate of bleeding episodes was calculated as: (Number of bleeding episodes/observed treatment period in days) * 365.25
Time Frame
12 months ± 14 days
Secondary Outcome Measure Information:
Title
Annualized Bleeding Rate by Treatment Regimen, Bleeding Etiology, and Bleed Type
Description
Spontaneous includes unknown/undermined etiology
Time Frame
12 months ± 14 days
Title
Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens by Bleeding Etiology, and Bleeding Type
Description
Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the t-test. The difference in mean transformed ABRs was used to perform statistical tests and generate p-values at a significance level of 5% Participants were Randomized to Receive 1 of the 2 Following Treatment Regimens: 1.On-Demand: FEIBA NF dose & dosing interval as prescribed by treating physician 2.Prophylaxis: 85 ± 15 U/kg of FEIBA NF every other day during 12-month prophylactic period
Time Frame
12 months ± 14 days
Title
Annualized Bleeding Rate for New Target Joints
Description
Target joints are ≥4 bleeds/6 months in any one of the following joints: ankles, knees, elbows, and hips; a target joint bleeding episode refers to an individual anatomical location.
Time Frame
12 months ± 14 days
Title
Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens: New Target Joints
Description
Annualized bleed rates (ABRs) were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using a two-sample, two-sided t-test. The difference in mean transformed ABRs was used to perform statistical tests and generate p-values at a significance level of 5%
Time Frame
12 months ± 14 days
Title
Number of New Target Joints
Description
Target Joints are defined as ≥4 bleeds/6 months in any one of the following joints: ankles, knees, elbows and hips
Time Frame
12 months ± 14 days
Title
Assessment of Objective Clinical Symptoms- Visual Analog Scale (VAS): Pain in Adolescents and Adults (≥12 Years Old)
Description
Pain caused by a bleeding episode in adolescents and adults (≥12 years old) was measured at pre-infusion (pre-inf) and at 6 ± 0.5 hours (h) and 24 ± 1 h post-infusion (post-inf) (after the last infusion given to treat a bleeding episode) on the VAS pain scale in millimeters from 0 (no pain) to 100 (worst possible pain). For analysis purposes, if short acting analgesics (duration of activity approximately 6 ± 0.5 h) were used, pain was assigned the highest possible score (100). Pain assessment occurred after each infusion related to single bleeding episodes. In case participants required an additional infusion within 24h, pain was assessed 6 ± 0.5 h and 24 ±1 h following the subsequent infusion. Change in VAS scores at 6 ± 0.5 h and 24 ±1 h post-infusion were also compared relative to pre-infusion VAS scores (ie, (pre-infusion VAS score) - (post-infusion VAS score)).
Time Frame
Throughout the study period, 12 months ± 14 days
Title
Assessment of Clinical Symptoms - Visual Analog Scale (VAS): Pain in Pediatrics (<12 Years Old)
Description
Pain caused by a bleeding episode (BE) in pediatric participants (<12 years old) was measured at pre-infusion (pre-inf) and at 6 ± 0.5 h and 24 ± 1 h post-infusion (post-inf) (after the last infusion given to treat a bleeding episode) using the children's VAS pain scale (a facial expression scale with one end marked as no pain and the opposite end marked as the worst possible pain). For analysis purposes, if short acting analgesics (duration of activity approximately 6 ± 0.5 h) were used, pain was assigned the highest possible score (worst possible pain). Scores on the children's VAS scale are presented as: -No Pain -Mild Pain -Moderate pain -Severe pain -Very severe pain
Time Frame
12 months ± 14 days
Title
Assessment of Clinical Symptoms - Range of Motion (ROM)
Description
ROM was measured using a goniometer for 3 key joints (ie, ankles, knees, and elbows) at screening, month 6, and termination (end of study visit)
Time Frame
12 months ± 14 days
Title
Assessment of Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 6 Hours
Description
Number of rAHF-PFM-treated bleeding episodes with an assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within ~6 hours of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within ~6 hours after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within ~6 hours after infusion. Requires >1 infusion for complete resolution; None: No improvement or condition worsens
Time Frame
6 h ± 30 min post-infusion
Title
Assessment of Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 24 Hours
Description
Number of rAHF-PFM-treated bleeding episodes with an assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within ~24 hours of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within ~24 hours after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within ~24 hours after infusion. Requires >1 infusion for complete resolution; None: No improvement or condition worsens
Time Frame
24 ± 1 h post-infusion
Title
Total Weight Adjusted Dose to Control a Bleeding Episode
Time Frame
12 months ± 14 days
Title
The Number of Bleeding Episode (BE) Which Required 1, 2, 3, or ≥4 Infusions to Control Bleeding
Time Frame
12 months ± 14 days
Title
Abnormal Activated Partial Thromboplastin Time (aPTT) Assay Results
Description
The normal reference range of values for aPTT is 22.8 - 31 seconds.
Time Frame
Screening visit, Month 3, Month 6, Month 9, and Termination visit
Title
Abnormal D-Dimer Assay Results
Description
The normal reference range of values for D-dimers is <500 ng/mL.
Time Frame
Screening visit, Month 3, Month 6, Month 9, and Termination visit
Title
Abnormal Fibrinogen Assay Results
Description
The normal reference range of values for fibrinogen is 200-400 mg/dL.
Time Frame
Screening visit, Month 3, Month 6, Month 9, and Termination visit
Title
Abnormal Fibrin Degradation Products (FDP) Assay Results
Description
The normal reference range of values for FDP is 0-5 ug/mL.
Time Frame
Screening visit, Month 3, Month 6, Month 9, and Termination visit
Title
Abnormal Prothrombin Fragment F 1.2 Assay Results
Description
The normal reference range of values for prothrombin fragment F 1.2 is 69-229 pmol/L.
Time Frame
Screening visit, Month 3, Month 6, Month 9, and Termination visit
Title
Abnormal Prothrombin Time Assay Results
Description
The normal reference range of values for PT is 9.7-12.3 sec.
Time Frame
Screening visit, Month 3, Month 6, Month 9, and Termination visit
Title
Abnormal Thrombin-Antithrombin III (TAT) Assay Results
Description
The normal reference range of values for TAT is 1-4.1 ug/L.
Time Frame
Screening visit, Month 3, Month 6, Month 9, and Termination visit
Title
Viral Serology From Screening Visit and Study Termination Visit: Hepatitis A, Hepatitis B, and Hepatitis C
Description
-Hepatitis A Virus Antibody (HAV Ab) -Hepatitis B Virus Core Antibody (HBcAb) -Hepatitis B Virus Surface Antibody (HBsAb) -Hepatitis B Virus Surface Antigen (HBsAg) -Hepatitis C Virus (HCV)
Time Frame
12 months ± 14 days
Title
Viral Serology From Screening Visit and Study Termination Visit: HIV-1/2 Antibody (Ab)
Time Frame
12 months ± 14 days
Title
Viral Serology From Screening Visit and Study Termination Visit: Parvovirus B19 IgG Antibody [IV]
Description
Normal range (0 - 0.89 IV); High (> 0.89 IV) - Parvovirus B19 IgG Antibody [IV] (Parvo IgG Ab)
Time Frame
12 months ± 14 days
Title
Viral Serology From Screening Visit and Study Termination Visit: Parvovirus B19 IgM Antibody [IV]
Description
Normal range (0 - 0.89 IV); High (> 0.89 IV) - Parvovirus B19 IgM Antibody [IV] (Parvo IgM Ab)
Time Frame
12 months ± 14 days
Title
Rate of Related Adverse Events (AEs) Per Year
Time Frame
12 months ± 14 days
Title
Rate of Related Adverse Events (AEs) During or Within 1 Hour of Infusion Per Year
Time Frame
12 months ± 14 days
Title
Number of Related Thromboembolic Adverse Events (AEs)
Time Frame
12 months ± 14 days
Title
Absolute Changes in Inhibitor Titer of Hemophilia A Participants With Shifts in Factor VIII (FVIII) Inhibitor Titer Levels
Description
Absolute Changes in Inhibitor Titer (or no change in low or high titer status): -Inhibitor Titer went from Low (≤5 BU) to Low (≤5 BU) -Inhibitor Titer went from Low (≤5 BU) to High (>5 BU) -Inhibitor Titer went from High (>5 BU) to Low (≤5 BU) -Inhibitor Titer went from High (>5 BU) to High (>5 BU)
Time Frame
12 months ± 14 days
Title
Absolute Changes in Inhibitor Titer of Hemophilia B Participants With Shifts in Factor IX (FIX) Inhibitor Titer Levels
Description
Absolute Changes in Inhibitor Titer (or no change in low or high titer status): -Inhibitor Titer went from Low (≤5 BU) to Low (≤5 BU) -Inhibitor Titer went from Low (≤5 BU) to High (>5 BU) -Inhibitor Titer went from High (>5 BU) to Low (≤5 BU) -Inhibitor Titer went from High (>5 BU) to High (>5 BU)
Time Frame
12 months ± 14 days
Title
Pharmacoeconomics: Annual Days Lost Due to Bleeding (Work or School)
Time Frame
12 months ± 14 days
Title
Pharmacoeconomics: Annual Number of Hospitalizations for Bleeding
Time Frame
12 months ± 14 days
Title
Pharmacoeconomics: Annual Number of Hospitalizations for Indwelling Line
Time Frame
12 months ± 14 days
Title
Pharmacoeconomics: Annual Number of Emergency Room Visits
Time Frame
12 months ± 14 days
Title
Pharmacoeconomics: Annual Number of Physician's Office Visits
Time Frame
12 months ± 14 days
Title
Pharmacoeconomics: Annual Total Length of Hospitalization for Bleeding
Time Frame
12 months ± 14 days
Title
Pharmacoeconomics: Annual Total Length of Hospitalization for Indwelling Line
Time Frame
12 months ± 14 days
Title
Pharmacoeconomics: Annual Total Number of Days Lost (Work or School)
Time Frame
12 months ± 14 days
Title
Health-Related Quality of Life (HRQoL): EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) Index Scores
Description
EQ-5D is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome. EQ-5D Index scores based on EQ-5D questionnaire were calculated for participants ≥14 years of age, at screening, 6 months, and at termination visit. Changes in scores at 6 months and termination were also calculated. A relatively higher score represents better quality of life.
Time Frame
12 months ± 14 days
Title
Hemophilia-specific Quality of Life Questionnaire for Adults (Haem-A-QoL) ≥ 16 Years Old
Description
The Haem-A-QoL instrument has been developed and used in Hemophilia A patients. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: Physical Health (PH), Sports & Leisure (S&L), School & Work (W&S), Dealing with Hemophilia (Dealing), Family Planning (FP), Feeling, Relationships (R'ships), Treatment, View, and Outlook for the Future (Future). A Haem-A-QoL Total Score (Total) was also calculated. For the Haem-A-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. Haem-A-QoL scores at screening, 6 months, and at termination visit were collected. Changes in scores at 6 months and termination were also calculated.
Time Frame
12 months ± 14 days
Title
Hemophilia-specific Quality of Life Questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Parent's Evaluation
Description
The Haemo-QoL is a quality of life (QoL) assessment instrument for children and adolescents with haemophilia. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: Physical Health (PH), Sports & School (S&S), Dealing with Hemophilia (Dealing), Family, Feeling, Relationships (R'ships), Treatment, View, Outlook for the Future (Future), Friends, Others, and Support. A Haemo-QoL Total Score (Total) was also calculated. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. Haemo-QoL scores at screening, 6 months, and at termination visit were collected. Changes in scores at 6 months and termination were also calculated.
Time Frame
12 months ± 14 days
Title
Hemophilia-specific Quality of Life Questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Child's Evaluation
Description
The Haemo-QoL is a quality of life (QoL) assessment instrument for children and adolescents with haemophilia. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: Physical Health (PH), Sports & School (S&S), Dealing with Hemophilia (Dealing), Family, Feeling, Relationships (R'ships), Treatment, View, Outlook for the Future (Future), Friends, Others, and Support. A Haemo-QoL Total Score (Total) was also calculated. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. Haemo-QoL scores at screening, 6 months, and at termination visit were collected. Changes in scores at 6 months and termination were also calculated.
Time Frame
12 months ± 14 days
Title
Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Adults and Adolescents ≥12 Years Old
Description
General pain was assessed using a VAS pain scale at screening, 6 months, and at termination. Unlike the VAS pain assessment for pain of bleeding episodes (Outcome above), this general pain assessment did not take use of analgesics into account. For the pain scale, a higher number indicates worse pain. The visual analog scale ranges from 0 to 100 where the endpoints are labeled 'Worst imaginable health state' (=0) and 'Best imaginable health state' (=100). A positive change from baseline indicates improvement. Change in VAS scores at 6 months and study termination were also compared relative to Baseline/Screening scores (ie, (Baseline/Screening VAS score) - (VAS score at 6 months and study termination).
Time Frame
Baseline, 6 months and 12 months ± 14 days
Title
Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Pediatrics <12 Years Old
Description
General pain was assessed using the children's VAS pain scale (a facial expression scale with one end marked as no pain and the opposite end marked as the worst possible pain). Assessments were done at the screening, 6 months, and termination visits. Scores on the children's VAS scale are presented as: -No Pain -Mild Pain -Moderate pain -Severe pain -Very severe pain Unlike the VAS pain assessment for pain of bleeding episodes (Outcome above), this general pain assessment did not take use of analgesics into account. Change in VAS scores at 6 months and study termination were also compared relative to Baseline/Screening scores (ie, (Baseline/Screening VAS score) - (VAS score at 6 months and study termination).
Time Frame
Baseline, 6 months and 12 months ± 14 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed and dated informed consent form by the participant or the participant's legally authorized representative The participant is ≥ 4 to ≤ 65 years of age The participant has a Karnofsky performance score of ≥ 60 Hemophilia A and B of any severity, with documented history of high-titer inhibitor (> 5 Bethesda unit (BU)) for at least 12 months; or, if inhibitor titer is ≤ 5 BU, and the participant is refractory with increased dosing of either factor VIII (FVIII) or factor IX (FIX), as demonstrated from the participant's medical history Currently being treated on an on-demand basis for treatment of bleeding episodes Adequate venous access, with or without central venous device ≥ 12 bleeding episodes requiring treatment with by-passing agents in the past 12 months, based on medical history Competent in-home treatment and infusion therapy Currently using bypassing agents (activated prothrombin complex concentrate (APCC) or recombinant activated factor VII (rFVIIa)) for treatment of bleeding episodes HCV-, either by antibody testing or polymerase chain reaction (PCR); or HCV+ with stable hepatic disease HIV-, or HIV+ with stable disease and CD4 count > 200 cells/mm3 at screening Female participant of childbearing potential, presents with a negative serum pregnancy test, and agrees to employ adequate birth control measures for the duration of the study Exclusion Criteria: Currently receiving immune tolerance induction (ITI) Currently on regular prophylactic therapy to prevent bleeding episodes Clinically symptomatic liver disease (e.g. diagnosis of cirrhosis [confirmed by liver biopsy], portal vein hypertension, ascites, prothrombin time (PT) 5 seconds above upper limit of normal) Platelet count < 100,000/ml Planned elective surgery during participation in this study Participant is currently participating in another clinical study and has received an investigational product or device within 30 days prior to study entry Planned use of pegylated or non-pegylated alpha-interferon with or without ribavirin for HCV infected participants or planned use of a protease inhibitor for HIV infected participants. Participants currently taking any of these medications for a 30-day course are eligible. Clinically significant increase in D-dimer levels from historical baseline and/or associated with chronic liver disease or clinically evident thromboembolic event Known hypersensitivity to anti-inhibitor coagulant complexes (AICCs) Currently treated with a systemic immunomodulating drug Prior history of thromboembolic event: acute myocardial infarction, deep vein thrombosis, or pulmonary embolism Diagnosis of advanced atherosclerosis, malignancy and/or other diseases that may increase the participant's risk of thromboembolic complications Clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
City
Chicago
State/Province
Illinois
Country
United States
City
Cleveland
State/Province
Ohio
Country
United States
City
Rio de Janeiro
State/Province
RJ
Country
Brazil
City
Sao Paulo
State/Province
SP
Country
Brazil
City
Sofia
Country
Bulgaria
City
Zagreb
Country
Croatia
City
Kanagawa
Country
Japan
City
Nara
Country
Japan
City
Wellington
Country
New Zealand
City
Krakow
Country
Poland
City
Warsaw
Country
Poland
City
Bucharest
Country
Romania
City
Timisoara
Country
Romania
City
Ekaterinburg
Country
Russian Federation
City
Kirov
Country
Russian Federation
City
Moscow
Country
Russian Federation
City
Lviv
Country
Ukraine

12. IPD Sharing Statement

Citations:
PubMed Identifier
23910578
Citation
Antunes SV, Tangada S, Stasyshyn O, Mamonov V, Phillips J, Guzman-Becerra N, Grigorian A, Ewenstein B, Wong WY. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia. 2014 Jan;20(1):65-72. doi: 10.1111/hae.12246. Epub 2013 Aug 1.
Results Reference
result

Learn more about this trial

Efficacy and Safety Study of Prophylactic Versus On-Demand Treatment With Feiba NF in Subjects With Hemophilia A or B and a High Titer Inhibitor

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