Clinical trial NCT01736475: Study Investigating a PEGylated Recombinant Factor VIII (BAX 855) for Hemophilia A (PROLONG-ATE Study)
Official title: A Phase 2/3, Multi-Center, Open Label Study of Efficacy, Safety, and Pharmacokinetics of PEGylated Recombinant Factor VIII (BAX 855) Administered for Prophylaxis and Treatment of Bleeding in Previously Treated Patients With Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Hemophilia A
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2012-11-29
Enrollment: 159
Sex: MALE
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


Eligibility criteria: Main Inclusion Criteria:

* 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 Exclusion Criteria:

* 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).

Primary outcomes:
measure: Annualized Bleeding Rate (ABR)
timeFrame: 9 months
Secondary outcomes:
measure: Rate of Success of BAX 855 for Treatment of Bleeding Episodes
timeFrame: 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.
measure: Average Number of BAX 855 Infusions Needed for the Treatment of Bleeding Episodes
timeFrame: 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].
measure: Number of Participants With ≤1, 2, 3, 4, 5, 6, or >6 Month Time Intervals Between Bleeding Episodes or no Bleeding Episodes
timeFrame: 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].
measure: Weight-adjusted Consumption of BAX 855 - Per Prophylactic Infusion and Pharmacokinetic (PK) Infusion
timeFrame: 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
measure: Weight-adjusted Consumption of BAX 855 - Per Treatment of Bleeding Episode (BE) and Per BE for Maintenance of Hemostasis
timeFrame: 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.
measure: Percentage of Participants With Adverse Events
timeFrame: 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].
measure: 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
timeFrame: 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].
measure: Patient Reported Outcomes: Haemo-SYM Questionnaire, Change in Score From Baseline to End of Study
timeFrame: 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].
measure: Patient Reported Outcomes - Short Form (SF)-36, Change From Baseline to End of Study
timeFrame: 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]
measure: Pharmacokinetics (Pk) - Plasma Half-life (One-stage Clotting Assay)
timeFrame: 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).
measure: Pharmacokinetics (Pk) - Mean Residence Time (One-stage Clotting Assay)
timeFrame: 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).
measure: Pharmacokinetics (Pk) - Total Body Clearance (One-stage Clotting Assay)
timeFrame: 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).
measure: Pharmacokinetics (Pk) - Incremental Recovery Over Time (One-stage Clotting Assay)
timeFrame: 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).
measure: Pharmacokinetics (Pk) - Area Under the Concentration Versus Time Curve From 0 to Infinity (AUC0-∞) (One-stage Clotting Assay)
timeFrame: 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).
measure: Pharmacokinetics (Pk) - Apparent Volume of Distribution at Steady State (Vss) (One-stage Clotting Assay)
timeFrame: 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).
measure: Pharmacokinetics (Pk) - Maximum Plasma Concentration (Cmax) (One-stage Clotting Assay)
timeFrame: 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).
measure: Pharmacokinetics (Pk) -Time to Maximum Concentration in Plasma (Tmax) (One-stage Clotting Assay)
timeFrame: 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).
measure: Change in Vital Signs From Screening - Temperature
timeFrame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination
measure: Change in Vital Signs From Screening - Pulse Rate
timeFrame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination
measure: Change in Vital Signs From Screening - Respiratory Rate
timeFrame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination
measure: Changes in Vital Signs From Screening - Blood Pressure
timeFrame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination
measure: Changes in Clinical Chemistry Laboratory Assessments From Screening - Albumin and Protein
timeFrame: Screening, week 2, week 4, month 3, study completion/termination
measure: Changes in Clinical Chemistry Laboratory Assessments From Screening - Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase
timeFrame: Screening, week 2, week 4, month 3, study completion/termination
measure: Changes in Clinical Chemistry Laboratory Assessments From Screening - Bicarbonate, Chloride, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN)
timeFrame: Screening, week 2, week 4, month 3, study completion/termination
measure: Changes in Clinical Chemistry Laboratory Assessments From Screening - Creatinine, and Bilirubin
timeFrame: Screening, week 2, week 4, month 3, study completion/termination
measure: Changes in Hematology Laboratory Assessments From Screening - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, and Leukocytes
timeFrame: Screening, week 2, week 4, month 3, study completion/termination
measure: Changes in Hematology Laboratory Assessments From Screening - Hematocrit
timeFrame: Screening, week 2, week 4, month 3, study completion/termination
measure: Changes in Hematology Laboratory Assessments From Screening - Hemoglobin
timeFrame: Screening, week 2, week 4, month 3, study completion/termination
measure: Changes in Hematology Laboratory Assessments From Screening - Erythrocytes
timeFrame: Screening, week 2, week 4, month 3, study completion/termination
measure: Changes in Lipid Panel Assessments From Screening - Cholesterol; High Density Lipoprotein (HDL); Low Density Lipoprotein (LDL); Triglycerides; and Very Low Density Lipoprotein (VLDL)
timeFrame: Screening, week 2, week 4, month 3, study completion/termination
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Gainesville
country: United States
facility: University of Florida, College of Medicine
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Peoria
country: United States
facility: Bleeding and Clotting Disorders Institute
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Medical School
state: Louisiana
city: Kansas City
country: United States
facility: Children's Mercy Hospitals & Clinics
state: Missouri
city: New York
country: United States
facility: Weill Cornell Medical College-New York Presbyterian Hospital
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Columbia
country: United States
facility: Palmetto Health
state: South Carolina
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Seattle
country: United States
facility: Puget Sound Blood Group
state: Washington
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Fremantle
country: Australia
facility: Fremantle Hospital
state: Western Australia
city: Nedlands
country: Australia
facility: Hollywood Specialist Centre
state: Western Australia
city: Linz
country: Austria
facility: Landes-Frauen-und Kinderklinik Linz
city: Vienna
country: Austria
facility: AKH - Medizinische Universität Wien
city: Sofia
country: Bulgaria
facility: SHAT of Oncohaematology Diseases
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Praha 5
country: Czechia
facility: Fakultni nemocnice v Motole
city: Duisburg
country: Germany
facility: Gerinnungszentrum Rhein-Ruhr
state: Nordrhein Westfalen
city: Berlin
country: Germany
facility: Vivantes Klinikum im Friedrichshain - Landsberger Allee
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Werlhof-Institut MVZ
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Tel Aviv
country: Israel
facility: Chaim Sheba Medical Center
city: Nagoya-shi
country: Japan
facility: Nagoya University Hospital
state: Aichi-Ken
city: Kitakyushu-shi
country: Japan
facility: University of Occupational and Environmental Health Hospital
state: Fukuoka-Ken
city: Hiroshima-shi
country: Japan
facility: Hiroshima University Hospital
state: Hiroshima-Ken
city: Nishinomiya-shi
country: Japan
facility: Hyogo College of Medicine Hospital
state: Hyogo-Ken
city: Kawasaki-shi
country: Japan
facility: St. Marianna University School of Medicine Hospital
state: Kanagawa-Ken
city: Kashihara-shi
country: Japan
facility: Nara Medical University Hospital
state: Nara-Ken
city: Shinjuku-ku
country: Japan
facility: Tokyo Medical University Hospital
state: Tokyo-To
city: Suginami-ku
country: Japan
facility: Ogikubo Hospital
state: Tokyo-To
city: Hwasun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Jeollanam-do
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Daejeon
country: Korea, Republic of
facility: Eulji University Hospital
city: Seoul
country: Korea, Republic of
facility: Kyung hee University Hospital at Gangdong
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santariskiu Clinics, Public Institution
city: Vilnius
country: Lithuania
facility: Children's Hospital, Affiliate of Vilnius University Hospital Santariskiu Klinikos
city: George Town
country: Malaysia
facility: Hospital Pulau Pinang
state: Pulau Pinang
city: Klang
country: Malaysia
facility: Hospital Tengku Ampuan Rahimah
state: Selangor
city: Kuala Lumpur
country: Malaysia
facility: Pusat Darah Negara
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Lodz
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im.M.Kopernika w Lodzi
city: Bucuresti
country: Romania
facility: Sanador SRL
city: Palma de Mallorca
country: Spain
facility: Hospital Universitari Son Espases
state: Baleares
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
state: La Coruña
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
state: Málaga
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Malmö
country: Sweden
facility: Skånes Universitetssjukhus, Malmö
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset, Solna
city: Zurich
country: Switzerland
facility: Universitatsspital Zurich
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Donetsk
country: Ukraine
facility: SI V.K.Gusak Emergency and Reconstructive Surgery Institute of NAMSU Center of IT
city: Lviv
country: Ukraine
facility: SI Institute of Blood Pathology and Transfusion Medicine of NAMSU
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
state: Avon
city: London
country: United Kingdom
facility: Royal Free Hospital
state: Greater London
city: London
country: United Kingdom
facility: St Thomas' Hospital
state: Greater London
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
state: Greater Manchester
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: Greater Manchester
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: Leicestershire
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: Oxfordshire
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Konkle BA, Stasyshyn O, Chowdary P, Bevan DH, Mant T, Shima M, Engl W, Dyck-Jones J, Fuerlinger M, Patrone L, Ewenstein B, Abbuehl B. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015 Aug 27;126(9):1078-85. doi: 10.1182/blood-2015-03-630897. Epub 2015 Jul 8.