Clinical trial NCT02585960: BAX 855 PK-guided Dosing
Official title: Phase 3, Prospective, Randomized, Multi-center Clinical Study Comparing the Safety and Efficacy of BAX 855 Following PK-guided Prophylaxis Targeting Two Different FVIII Trough Levels in Subjects With Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia A
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Baxalta Innovations GmbH, now part of Shire
First posted: 2015-10-26
Enrollment: 135
Sex: ALL
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 1. To compare the efficacy and safety of pharmacokinetic (PK)-guided treatment with BAX 855 targeting FVIII trough levels of 1-3% and approximately 10% (8-12%)
2. To further characterize pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BAX 855


Eligibility criteria: INCLUSION CRITERIA:

* Participants transitioning from another BAX 855 study who meet ALL of the following criteria are eligible for this study:

  1. Participant has completed the end of study visit of a BAX 855 study or is transitioning from the ongoing Baxalta Continuation Study 261302.
  2. Participant is either receiving on-demand treatment or prophylactic treatment with BAX 855 and had an Annual Bleed Rate (ABR) of ≥ 2 documented and treated during the past 12 months.
  3. Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm\^3, as confirmed by central laboratory.
  4. Participant is willing and able to comply with the requirements of the protocol.
* Newly recruited participants (ie not transitioning from another BAX 855 study) including BAX855 naïve participants who meet ALL of the following criteria are eligible for this study:

  1. Participant has severe hemophilia A (FVIII clotting activity \< 1%) as confirmed by central laboratory OR by historically documented FVIII clotting activity performed by a certified clinical laboratory, optionally supported by a FVIII gene mutation consistent with severe hemophilia A
  2. Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥ 150 documented exposure days (EDs)
  3. Participant is either receiving on-demand treatment or prophylactic treatment and had an annual bleeding rate of ≥ 2 documented and treated during the past 12 months.
  4. Participant has a Karnofsky performance score of ≥ 60 at screening
  5. Participant is HIV-; or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm\^3, as confirmed by central laboratory at screening
  6. Participant is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis
  7. If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study
  8. Participant is willing and able to comply with the requirements of the protocol.

EXCLUSION CRITERIA:

* Participants transitioning from another BAX 855 study who meet ANY of the following criteria are not eligible for this study:

  1. Participant has developed a confirmed inhibitory antibody to FVIII with a titer of ≥ 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at the central laboratory during the course of the previous BAX 855 study.
  2. Participant has been diagnosed with an acquired hemostatic defect other than hemophilia A.
  3. The participant's weight is \< 35 kg or \> 100 kg.
  4. Participant's platelet count is \< 100,000/mL.
  5. Participant has an abnormal renal function (serum creatinine \> 1.5 times the upper limit of normal).
  6. Participant has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal.
  7. Participant is scheduled to receive a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy during the study.
  8. Participant has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant's safety or compliance.
  9. Participant is planning to take part in any other clinical study during the course of the study.
  10. Participant is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

Newly recruited participants (ie not transitioning from another BAX 855 study) who meet ANY of the following criteria are not eligible for this study:

1. Participant has detectable FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening.
2. Participant has a history of confirmed FVIII inhibitors with a titer ≥ 0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed with the respective cut-off in the local laboratory) at any time prior to screening.
3. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).
4. The participant's weight is \< 35 kg or \> 100 kg.
5. Participant's platelet count is \< 100,000/mL.
6. Participant has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80.
7. Participant has severe chronic hepatic dysfunction \[eg, ≥ 5 times upper limit of normal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), as confirmed by central laboratory at screening, or a documented INR \> 1.5\].
8. Participant has severe renal impairment (serum creatinine \> 1.5 times the upper limit of normal).
9. Participant has current or recent (\< 30 days) use of other pegylated drugs prior to study participation or is scheduled to use such drugs during study participation.
10. Participant is scheduled to receive during the course of the study, a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy.
11. Participant has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.
12. Participant has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.
13. Participant is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

Primary outcomes:
measure: Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months
timeFrame: Day 183 to Day 364 (6 months)
Secondary outcomes:
measure: Total Annualized Bleeding Rate for Second Six Months
timeFrame: Day 183 to Day 364 (6 months)
measure: Annualized Spontaneous Bleeding Rate for Second Six Months
timeFrame: Day 183 to Day 364 (6 months)
measure: Annualized Traumatic Bleeding Rate for Second Six Months
timeFrame: Day 183 to Day 364 (6 months)
measure: Annualized Joint Bleeding Rate (AJBR) for Second Six Months
timeFrame: Day 183 to Day 364 (6 months)
measure: Total Weight-adjusted Consumption of BAX 855
timeFrame: From start of study treatment up to 12 months (completion or termination)
measure: Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions
timeFrame: 8 hours after study drug administration
measure: Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution
timeFrame: From start of study treatment up to bleed resolution (up to 12 months)
measure: Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution
timeFrame: From start of study treatment up to 12 months (completion or termination)
measure: Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score
timeFrame: Baseline, Month 12
measure: Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds
timeFrame: Day 0 through discharge or 14 days post-surgery
measure: Blood Loss Per Participant in Case of Surgery
timeFrame: Day 0 through discharge or 14 days post-surgery
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From start of study treatment up to 12 months (completion or termination)
measure: Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events
timeFrame: From start of study treatment up to 12 months (completion or termination)
measure: Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events
timeFrame: From start of study treatment up to 12 months (completion or termination)
measure: Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein
timeFrame: From start of study treatment up to 12 months (completion or termination)
measure: Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey
timeFrame: Baseline, Month 12 (completion or termination)
measure: Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf)
timeFrame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
measure: Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855
timeFrame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
measure: Plasma Half-life (T1/2) of BAX 855
timeFrame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
measure: Mean Residence Time (MRT) of BAX 855
timeFrame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
measure: Maximum Plasma Concentration (Cmax) of BAX 855
timeFrame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
measure: Time to Maximum Concentration of BAX 855 in Plasma (Tmax)
timeFrame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
measure: Total Body Clearance (CL) of BAX 855
timeFrame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
measure: Volume of Distribution at Steady State (Vss)
timeFrame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
measure: Incremental Recovery (IR) Over Time
timeFrame: Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Tucson
country: United States
facility: Arizona Hemophilia & Thrombosis Center, located within The University of Arizona Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
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: Emory University-ECC
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville KCPCRU
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Houston
country: United States
facility: Gulf States Hemophilia Centre
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Herston
country: Australia
facility: Royal Brisbane Women's Hospital
state: Queensland
city: Nedlands
country: Australia
facility: The Perth Blood Institute
state: Western Australia
city: Vienna
country: Austria
facility: AKH - Medizinische Universität Wien
city: Plovdiv
country: Bulgaria
facility: UMHAT "Sv. Georgi", EAD
city: Sofia
country: Bulgaria
facility: UMHAT 'Tsaritsa Yoanna - ISUL', EAD
city: Varna
country: Bulgaria
facility: MHAT 'Sv. Marina', EAD, Clinic of Clinical Hematology
city: Nice
country: France
facility: CHU Nice- Service hematologie
state: Alpes Maritimes
city: Brest Cedex
country: France
facility: Hôpital Morvan
state: Finistere
city: Rennes cedex 09
country: France
facility: CHU Rennes - Hopital Pontchaillou
state: Ille Et Vilaine
city: Caen
country: France
facility: CHU de Caen - Hôpital Côte de Nacre
city: Rouen
country: France
facility: CHU Charles Nicolle
city: Mörfelden-Walldorf
country: Germany
facility: HZRM Hamophilie Zentrum Rhein Main GmbH
state: Hessen
city: Bonn
country: Germany
facility: Inst. f. Experimentelle Hamatologie u. Transfusionsmedizin
state: Nordrhein Westfalen
city: Duisburg
country: Germany
facility: COAGULATION RESEARCH CENTRE GmbH
state: Nordrhein Westfalen
city: Berlin
country: Germany
facility: Hamophiliezentrum/Gerinnungssprechstunde
city: Leipzig
country: Germany
facility: MVZ Labor Dr. Reising-Ackermann
city: Hong Kong
country: Hong Kong
facility: University of Hong Kong
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
city: Budapest
country: Hungary
facility: Magyar Honvedseg EK
city: Debrecen
country: Hungary
facility: DE OEC Belgyógyászati Int
city: Pecs
country: Hungary
facility: PTE ÁOK
city: Tel-Hashomer
country: Israel
facility: Chaim Sheba Medical Center
city: Castelfranco Veneto
country: Italy
facility: UOC Ematologia, Azienda ULSS 8 Asolo, Regione Veneto
state: Treviso
city: Catania
country: Italy
facility: Presidio Osped. Ferrarotto
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Roma
country: Italy
facility: Umberto I Pol. di Roma-Università di Roma La Sapienza
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli
city: Torino
country: Italy
facility: AOU Citta della Salute e della Scienza - Presidio Molinette
city: Vicenza
country: Italy
facility: ULSS n. 6 "Vicenza"
city: Ampang
country: Malaysia
facility: Hospital Ampang
state: Kuala Lumpur
city: Kota Kinabalu
country: Malaysia
facility: Hospital Queen Elizabeth
state: Sabah
city: Kuala Lumpur
country: Malaysia
facility: Hospital Kuala Lumpur
city: Melaka
country: Malaysia
facility: Hospital Melaka
city: Pulau Pinang
country: Malaysia
facility: Hospital Pulau Pinang
city: Oslo
country: Norway
facility: Oslo Universitetssykehus HF
city: Lodz
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. Mikolaja Kopernika, Klinika Hematologii
city: Poznań
country: Poland
facility: Alvamed
city: Warszawa
country: Poland
facility: Instytut Hematologii Ii Transfuzjologii
city: Wroclaw
country: Poland
facility: SP Szpital Kliniczny Nr 1 we Wroclawiu
city: Brasov
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Brasov
city: Cluj Napoca
country: Romania
facility: Institutul Oncologic ClNa.
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital- Parent
city: Singapore
country: Singapore
facility: KK Women's And Children's Hospital
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: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Gothenburg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Adana
country: Turkey
facility: Acibadem Hastanesi
city: Antalya
country: Turkey
facility: Akdeniz University
city: Istanbul
country: Turkey
facility: Istanbul University
city: Izmir
country: Turkey
facility: Ege University
city: Kyiv
country: Ukraine
facility: NChSH Okhmatdyt of MoHU Center of Children Oncohematology and Bone Marrow Transplantation
city: Kyiv
country: Ukraine
facility: Kyiv CCH #9 Dept of Surgery City SPC of Diagnostics & Treatment of Patients with HP
city: Lviv
country: Ukraine
facility: SI Institute of Blood Pathology and Transfusion Medicine of NAMSU
city: Poltava
country: Ukraine
facility: M.V. Sklifosovskyi Poltava RCH Dept of Gematology HSEIU Ukrainian Medical Stomatological Academy
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: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: Greater Manchester
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: Hampshire
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: Leicestershire
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: Oxfordshire
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: West Glamorgan
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Klamroth R, Windyga J, Radulescu V, Collins PW, Stasyshyn O, Ibrahim HM, Engl W, Tangada SD, Savage W, Ewenstein B. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study. Blood. 2021 Apr 1;137(13):1818-1827. doi: 10.1182/blood.2020005673.