Study Investigating a PEGylated Recombinant Factor VIII (BAX 855) for Hemophilia A (PROLONG-ATE Study)
- Conditions
- Hemophilia A
- Interventions
- Biological: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free MethodBiological: PEGylated Recombinant Factor VIII
- Registration Number
- NCT01736475
- Lead Sponsor
- Baxalta now part of Shire
- Brief Summary
To assess efficacy and safety, including immunogenicity of BAX 855 administered as prophylaxis and as on-demand therapy in adult and adolescent (12-65 years) previously treated patients (PTPs) with severe hemophilia A To determine the pharmacokinetic (PK) parameters of BAX 855.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 159
- Participant and/or legal representative has/have voluntarily provided signed informed consent
- Participant is 12 to 65 years old at the time of screening
- Participant is male with severe hemophilia A (Factor VIII (FVIII) clotting activity < 1%) as confirmed by central laboratory at screening after the appropriate washout period or a documented FVIII clotting activity <1%
- Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥150 documented exposure days (EDs)
- Participant is currently receiving prophylaxis or on-demand therapy with FVIII
- Participant is willing and able to comply with the requirements of the protocol
Main
- Participant has detectable FVIII inhibitory antibodies (≥ 0.6 Bethesda Units (BU) using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening
- Participant has history of FVIII inhibitory antibodies (≥ 0.4 BU using the Nijmegen modification of the Bethesda assay or ≥ 0.6 BU using the Bethesda assay) at any time prior to screening
- Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Prophylaxis PEGylated Recombinant Factor VIII - On-demand PEGylated Recombinant Factor VIII - Prophylaxis Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method -
- Primary Outcome Measures
Name Time Method Annualized Bleeding Rate (ABR) 9 months Comparisons between prophylactic and on-demand treatment were based on ABR estimates from a negative binomial regression model, taking into account the treatment regimen, target joints and age at screening, and duration of the observation period for efficacy.
- Secondary Outcome Measures
Name Time Method Weight-adjusted Consumption of BAX 855 - Per Prophylactic Infusion and Pharmacokinetic (PK) Infusion Prophylactic Infusion: ≥50 exposure days or 6 months (±2 weeks), whichever occurs last. PK Infusion: PK #1 Pre-infusion within 30 minutes; Post-infusion 10 min, and 0.5, 1, 3, 6, 24, 32, 48, 56 hours (h). PK #2 also at Post-infusion 96h Patient Reported Outcomes - Short Form (SF)-36, Change From Baseline to End of Study Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm] Change from Baseline to End of Study for SF-36 Questionnaire is provided. Scores for individual SF-36 categories range from 0 to 100 with higher scores representing better health. Given that higher scores indicate better health-related quality of life (HRQoL) and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates a worsening of HRQoL.
Average Number of BAX 855 Infusions Needed for the Treatment of Bleeding Episodes From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm]. Weight-adjusted Consumption of BAX 855 - Per Treatment of Bleeding Episode (BE) and Per BE for Maintenance of Hemostasis Treatment of Bleeding Episode (BE): Minor/Moderate BE every 12 to 24 hours until bleeding is resolved; Major BE every 8 to 12 hours until bleeding is resolved. Per BE for Maintenance of Hemostasis: within 48 hours after bleeding episode resolution. Infusions per bleeding episode for maintenance of hemostasis only includes infusions following the resolution of a bleed to maintain hemostasis.
Rate of Success of BAX 855 for Treatment of Bleeding Episodes At least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm. Success in the control of bleeding was defined as a rating of excellent or good using the Efficacy Rating Scale for Treatment of Bleeding Episodes measured 24 hours after initiation of treatment for the bleeding episode. EXCELLENT: Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusions to maintain hemostasis would not affect this scoring. GOOD: Definite pain relief and/or improvement in signs of bleeding after a single infusion. Possibly requires more than 1 infusion for complete resolution. FAIR: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion. Required more than 1 infusion for complete resolution. NONE: No improvement or condition worsens.
Percentage of Participants With Adverse Events From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm]. Adverse Events (AEs) and Serious Adverse Events (SAEs)
Pharmacokinetics (Pk) - Apparent Volume of Distribution at Steady State (Vss) (One-stage Clotting Assay) Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). The apparent volume of distribution at steady state (Vss) will be calculated as: Vss = Clearance \* Mean Residence Time. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Change in Vital Signs From Screening - Respiratory Rate Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination Changes in Vital Signs From Screening - Blood Pressure Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP)
Changes in Clinical Chemistry Laboratory Assessments From Screening - Bicarbonate, Chloride, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN) Screening, week 2, week 4, month 3, study completion/termination Number of Participants With ≤1, 2, 3, 4, 5, 6, or >6 Month Time Intervals Between Bleeding Episodes or no Bleeding Episodes From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm]. Interval between Bleeds in months was calculated as: Observation period for efficacy (in days)/(number of bleeds)\*(12/365.2425)
Immunogenicity - Number of Participants With Positive Inhibitory Antibodies to FVIII, Binding Antibodies to FVIII, PEG-VIII, PEG and Anti-CHO Antibodies at Study Completion/Termination From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm]. Number of participants who received BAX855, with immunogenicity data from study completion/termination visit. FVIII = factor VIII; PEG-VIII = polyethylene glycol-factor VIII; Anti-CHO = Anti-Chinese hamster ovary
Patient Reported Outcomes: Haemo-SYM Questionnaire, Change in Score From Baseline to End of Study Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm]. The HAEMO-SYM has two subscales: pain and bleeds. HAEMO-SYM subscale scores are calculated by taking the mean of the items in each subscale and transforming them to a 0 (none or absent) to 100 (very severe) scale. Given that higher scores indicate more severe symptoms on the Haemo-SYM and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates an improvement (reduction in symptoms). Conversely, a positive change score indicates worsening symptoms.
Pharmacokinetics (Pk) - Area Under the Concentration Versus Time Curve From 0 to Infinity (AUC0-∞) (One-stage Clotting Assay) Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). Calculated by WinNonlin NCA (Model 201, calculation method: Linear Trapezoidal Linear/Log Interpolation). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Pharmacokinetics (Pk) -Time to Maximum Concentration in Plasma (Tmax) (One-stage Clotting Assay) Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). Tmax in hours will be defined as the time to reach Cmax. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Change in Vital Signs From Screening - Temperature Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination Changes in Hematology Laboratory Assessments From Screening - Hemoglobin Screening, week 2, week 4, month 3, study completion/termination Pharmacokinetics (Pk) - Plasma Half-life (One-stage Clotting Assay) Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). Terminal half-life calculated as log_e2/λz where λz is the terminal elimination rate constant. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Pharmacokinetics (Pk) - Total Body Clearance (One-stage Clotting Assay) Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). Clearance in dL/(kg.h) will be calculated as the dose in IU/kg divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Pharmacokinetics (Pk) - Maximum Plasma Concentration (Cmax) (One-stage Clotting Assay) Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Changes in Clinical Chemistry Laboratory Assessments From Screening - Creatinine, and Bilirubin Screening, week 2, week 4, month 3, study completion/termination Pharmacokinetics (Pk) - Mean Residence Time (One-stage Clotting Assay) Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). The mean residence time (MRT) w as calculated as total area under the moment curve divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Changes in Clinical Chemistry Laboratory Assessments From Screening - Albumin and Protein Screening, week 2, week 4, month 3, study completion/termination Pharmacokinetics (Pk) - Incremental Recovery Over Time (One-stage Clotting Assay) Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). Incremental recovery (IR) in (IU/dL)/ (IU/kg) calculated as: IR = (Cmax- (C pre-infusion)) / (Dose/kg), where C =concentration. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).
Change in Vital Signs From Screening - Pulse Rate Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination Changes in Clinical Chemistry Laboratory Assessments From Screening - Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase Screening, week 2, week 4, month 3, study completion/termination Alkaline Phosphatase (Alk Phos); Alanine Aminotransferase (Ala Amino); Aspartate Aminotransferase (Asp Amino)
Changes in Lipid Panel Assessments From Screening - Cholesterol; High Density Lipoprotein (HDL); Low Density Lipoprotein (LDL); Triglycerides; and Very Low Density Lipoprotein (VLDL) Screening, week 2, week 4, month 3, study completion/termination Changes in Hematology Laboratory Assessments From Screening - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, and Leukocytes Screening, week 2, week 4, month 3, study completion/termination Changes in Hematology Laboratory Assessments From Screening - Hematocrit Screening, week 2, week 4, month 3, study completion/termination Changes in Hematology Laboratory Assessments From Screening - Erythrocytes Screening, week 2, week 4, month 3, study completion/termination
Trial Locations
- Locations (72)
Wojewodzki Szpital Specjalistyczny im.M.Kopernika w Lodzi
🇵🇱Lodz, Poland
Tri-Service General Hospital
🇨🇳Taipei, Taiwan
Palmetto Health
🇺🇸Columbia, South Carolina, United States
AKH - Medizinische Universität Wien
🇦🇹Vienna, Austria
SHAT of Oncohaematology Diseases
🇧🇬Sofia, Bulgaria
SI V.K.Gusak Emergency and Reconstructive Surgery Institute of NAMSU Center of IT
🇺🇦Donetsk, Ukraine
Fremantle Hospital
🇦🇺Fremantle, Western Australia, Australia
Hollywood Specialist Centre
🇦🇺Nedlands, Western Australia, Australia
Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
The Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
University of Utah Health Sciences Center
🇺🇸Salt Lake City, Utah, United States
Puget Sound Blood Group
🇺🇸Seattle, Washington, United States
University of Colorado
🇺🇸Aurora, Colorado, United States
Bleeding and Clotting Disorders Institute
🇺🇸Peoria, Illinois, United States
Weill Cornell Medical College-New York Presbyterian Hospital
🇺🇸New York, New York, United States
The Alfred Hospital
🇦🇺Clayton, Victoria, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Landes-Frauen-und Kinderklinik Linz
🇦🇹Linz, Austria
Fakultni nemocnice Brno
🇨🇿Brno, Czechia
Fakultni nemocnice Olomouc
🇨🇿Olomouc, Czechia
Fakultni nemocnice v Motole
🇨🇿Praha 5, Czechia
Gerinnungszentrum Rhein-Ruhr
🇩🇪Duisburg, Nordrhein Westfalen, Germany
Rambam Health Care Campus
🇮🇱Haifa, Israel
Universitaetsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Vivantes Klinikum im Friedrichshain - Landsberger Allee
🇩🇪Berlin, Germany
Werlhof-Institut MVZ
🇩🇪Hannover, Germany
Nagoya University Hospital
🇯🇵Nagoya-shi, Aichi-Ken, Japan
Chaim Sheba Medical Center
🇮🇱Tel Aviv, Israel
University of Occupational and Environmental Health Hospital
🇯🇵Kitakyushu-shi, Fukuoka-Ken, Japan
Hyogo College of Medicine Hospital
🇯🇵Nishinomiya-shi, Hyogo-Ken, Japan
St. Marianna University School of Medicine Hospital
🇯🇵Kawasaki-shi, Kanagawa-Ken, Japan
Skånes Universitetssjukhus, Malmö
🇸🇪Malmö, Sweden
Hiroshima University Hospital
🇯🇵Hiroshima-shi, Hiroshima-Ken, Japan
Nara Medical University Hospital
🇯🇵Kashihara-shi, Nara-Ken, Japan
Ogikubo Hospital
🇯🇵Suginami-ku, Tokyo-To, Japan
Tokyo Medical University Hospital
🇯🇵Shinjuku-ku, Tokyo-To, Japan
Eulji University Hospital
🇰🇷Daejeon, Korea, Republic of
Pusan National University Hospital
🇰🇷Busan, Korea, Republic of
Ulsan University Hospital
🇰🇷Ulsan, Korea, Republic of
Chonnam National University Hwasun Hospital
🇰🇷Hwasun, Jeollanam-do, Korea, Republic of
Vilnius University Hospital Santariskiu Clinics, Public Institution
🇱🇹Vilnius, Lithuania
Children's Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos
🇱🇹Vilnius, Lithuania
Kyung hee University Hospital at Gangdong
🇰🇷Seoul, Korea, Republic of
Hospital Pulau Pinang
🇲🇾George Town, Pulau Pinang, Malaysia
Hospital Tengku Ampuan Rahimah
🇲🇾Klang, Selangor, Malaysia
Pusat Darah Negara
🇲🇾Kuala Lumpur, Malaysia
Academisch Medisch Centrum
🇳🇱Amsterdam, Netherlands
Uniwersyteckie Centrum Kliniczne
🇵🇱Gdansk, Poland
Sanador SRL
🇷🇴Bucuresti, Romania
Complejo Hospitalario Universitario A Coruña
🇪🇸A Coruña, La Coruña, Spain
Hospital Regional Universitario de Malaga
🇪🇸Malaga, Málaga, Spain
Karolinska Universitetssjukhuset, Solna
🇸🇪Stockholm, Sweden
Hospital Universitari Son Espases
🇪🇸Palma de Mallorca, Baleares, Spain
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Universitatsspital Zurich
🇨🇭Zurich, Switzerland
SI Institute of Blood Pathology and Transfusion Medicine of NAMSU
🇺🇦Lviv, Ukraine
Bristol Royal Hospital for Children
🇬🇧Bristol, Avon, United Kingdom
Manchester Royal Infirmary
🇬🇧Manchester, Greater Manchester, United Kingdom
Royal Free Hospital
🇬🇧London, Greater London, United Kingdom
Royal Manchester Children's Hospital
🇬🇧Manchester, Greater Manchester, United Kingdom
Churchill Hospital
🇬🇧Oxford, Oxfordshire, United Kingdom
Leicester Royal Infirmary
🇬🇧Leicester, Leicestershire, United Kingdom
Penn State Milton S. Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
University of Florida, College of Medicine
🇺🇸Gainesville, Florida, United States
Tulane University Medical School
🇺🇸New Orleans, Louisiana, United States
University of North Carolina Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
University of Kentucky Medical Center
🇺🇸Lexington, Kentucky, United States
Children's Mercy Hospitals & Clinics
🇺🇸Kansas City, Missouri, United States
University of Louisville Hospital
🇺🇸Louisville, Kentucky, United States
St Thomas' Hospital
🇬🇧London, Greater London, United Kingdom