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

Phase 3

Completed

Conditions: Hemophilia A
Hemophilia B
Hemophilia A or B With Inhibitors

Interventions: Biological: Factor VIII Inhibitor Bypassing Activity (nanofiltered, vapor heat-treated)

Registration Number: NCT00851721

Lead Sponsor: Baxalta now part of Shire

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
On-demand arm	Factor VIII Inhibitor Bypassing Activity (nanofiltered, vapor heat-treated)	-
Prophylaxis arm	Factor VIII Inhibitor Bypassing Activity (nanofiltered, vapor heat-treated)	-

Primary Outcome Measures

Name	Time	Method
Reduction in Annualized Bleeding Episode Rate (ABR) Among Participants Receiving Prophylactic Treatment as Compared to Those Treated On-demand	12 months ± 14 days	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

Name	Time	Method
Number of New Target Joints	12 months ± 14 days	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)	Throughout the study period, 12 months ± 14 days	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)).
Annualized Bleeding Rate by Treatment Regimen, Bleeding Etiology, and Bleed Type	12 months ± 14 days	Spontaneous includes unknown/undermined etiology
Assessment of Clinical Symptoms - Range of Motion (ROM)	12 months ± 14 days	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)
Total Weight Adjusted Dose to Control a Bleeding Episode	12 months ± 14 days
Abnormal D-Dimer Assay Results	Screening visit, Month 3, Month 6, Month 9, and Termination visit	The normal reference range of values for D-dimers is \<500 ng/mL.
Abnormal Fibrin Degradation Products (FDP) Assay Results	Screening visit, Month 3, Month 6, Month 9, and Termination visit	The normal reference range of values for FDP is 0-5 ug/mL.
Number of Related Thromboembolic Adverse Events (AEs)	12 months ± 14 days
Absolute Changes in Inhibitor Titer of Hemophilia A Participants With Shifts in Factor VIII (FVIII) Inhibitor Titer Levels	12 months ± 14 days	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)
The Number of Bleeding Episode (BE) Which Required 1, 2, 3, or ≥4 Infusions to Control Bleeding	12 months ± 14 days
Viral Serology From Screening Visit and Study Termination Visit: HIV-1/2 Antibody (Ab)	12 months ± 14 days
Rate of Related Adverse Events (AEs) During or Within 1 Hour of Infusion Per Year	12 months ± 14 days
Annualized Bleeding Rate for New Target Joints	12 months ± 14 days	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.
Abnormal Fibrinogen Assay Results	Screening visit, Month 3, Month 6, Month 9, and Termination visit	The normal reference range of values for fibrinogen is 200-400 mg/dL.
Abnormal Prothrombin Fragment F 1.2 Assay Results	Screening visit, Month 3, Month 6, Month 9, and Termination visit	The normal reference range of values for prothrombin fragment F 1.2 is 69-229 pmol/L.
Abnormal Thrombin-Antithrombin III (TAT) Assay Results	Screening visit, Month 3, Month 6, Month 9, and Termination visit	The normal reference range of values for TAT is 1-4.1 ug/L.
Viral Serology From Screening Visit and Study Termination Visit: Parvovirus B19 IgM Antibody [IV]	12 months ± 14 days	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	12 months ± 14 days
Pharmacoeconomics: Annual Number of Emergency Room Visits	12 months ± 14 days
Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Adults and Adolescents ≥12 Years Old	Baseline, 6 months and 12 months ± 14 days	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).
Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens by Bleeding Etiology, and Bleeding Type	12 months ± 14 days	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
Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens: New Target Joints	12 months ± 14 days	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%
Assessment of Clinical Symptoms - Visual Analog Scale (VAS): Pain in Pediatrics (<12 Years Old)	12 months ± 14 days	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 Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 24 Hours	24 ± 1 h post-infusion	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
Abnormal Activated Partial Thromboplastin Time (aPTT) Assay Results	Screening visit, Month 3, Month 6, Month 9, and Termination visit	The normal reference range of values for aPTT is 22.8 - 31 seconds.
Abnormal Prothrombin Time Assay Results	Screening visit, Month 3, Month 6, Month 9, and Termination visit	The normal reference range of values for PT is 9.7-12.3 sec.
Assessment of Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 6 Hours	6 h ± 30 min post-infusion	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
Pharmacoeconomics: Annual Number of Hospitalizations for Indwelling Line	12 months ± 14 days
Pharmacoeconomics: Annual Total Number of Days Lost (Work or School)	12 months ± 14 days
Hemophilia-specific Quality of Life Questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Child's Evaluation	12 months ± 14 days	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.
Viral Serology From Screening Visit and Study Termination Visit: Hepatitis A, Hepatitis B, and Hepatitis C	12 months ± 14 days	-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: Parvovirus B19 IgG Antibody [IV]	12 months ± 14 days	Normal range (0 - 0.89 IV); High (\> 0.89 IV) - Parvovirus B19 IgG Antibody \[IV\] (Parvo IgG Ab)
Pharmacoeconomics: Annual Number of Hospitalizations for Bleeding	12 months ± 14 days
Pharmacoeconomics: Annual Total Length of Hospitalization for Indwelling Line	12 months ± 14 days
Hemophilia-specific Quality of Life Questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Parent's Evaluation	12 months ± 14 days	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.
Pharmacoeconomics: Annual Days Lost Due to Bleeding (Work or School)	12 months ± 14 days
Health-Related Quality of Life (HRQoL): EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) Index Scores	12 months ± 14 days	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	12 months ± 14 days	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.
Absolute Changes in Inhibitor Titer of Hemophilia B Participants With Shifts in Factor IX (FIX) Inhibitor Titer Levels	12 months ± 14 days	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 Number of Physician's Office Visits	12 months ± 14 days
Pharmacoeconomics: Annual Total Length of Hospitalization for Bleeding	12 months ± 14 days
Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Pediatrics <12 Years Old	Baseline, 6 months and 12 months ± 14 days	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).