Clinical trial NCT02716194: BAX 826 Dose-Escalation Safety Study
Official title: A Phase 1, Prospective, Open Label, Two Period, Fixed Sequence, Dose-Escalation Study of the PK and Safety of BAX 826 (PSA-rFVIII) in Previously Treated Patients With Severe (FVIII <1%) Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hemophilia A
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2016-03-23
Enrollment: 40
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 1. To assess tolerability and safety of BAX 826 after a single infusion in previously treated patients (PTPs) with severe hemophilia A
2. To determine the pharmacokinetic (PK) parameters of BAX 826 compared to ADVATE
3. To evaluate immunogenicity of polysialic acid linked to Factor VIII (FVIII)


Eligibility criteria: Inclusion Criteria:

1. Previously treated male participants aged 18 to 65 years (inclusive) at the time of screening
2. Diagnosis of severe hemophilia A (Factor VIII level \<1%)
3. Previously treated with FVIII concentrates for ≥150 documented Exposure Days (EDs)
4. Karnofsky performance score of ≥60
5. Human immunodeficiency virus negative (HIV-); or HIV+ with stable disease
6. Hepatitis C virus negative (HCV-); or HCV+ with chronic stable hepatitis as assessed by the investigator
7. Able to understand and have provided written informed consent including signature on an informed consent form (ICF) approved by an ethics committee (EC)
8. Have provided written authorization for use and disclosure of protected health information
9. Agree to abide by the study schedule and to return for the required assessments
10. Willing and able to comply with the requirements of the protocol

Exclusion Criteria:

1. Detectable FVIII inhibitor at screening, with a titer ≥0.6 Bethesda Unit (BU)
2. Documented history of FVIII inhibitors with a titer ≥0.4 BU at any time prior to screening
3. Known clinical hypersensitivity towards mouse or hamster proteins or to polysialic acid (PSA)
4. Scheduled elective surgery during study participation
5. Severe chronic hepatic dysfunction
6. Severe renal impairment
7. Currently receiving, or has recently received (less than 3 months prior to study participation), or is scheduled to receive during the course of the study, other PSA-ylated drugs
8. Have received another investigational drug within 30 days prior to study entry and/or is scheduled to receive additional investigational drug during the course of the study in the context of another investigational drug study
9. Diagnosis of an inherited or acquired hemostatic defect other than hemophilia A
10. Currently receiving, or scheduled to receive during the course of the study, an immune-modulating drug other than antiretroviral chemotherapy
11. Has a clinically significant medical, psychiatric or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect the safety or compliance of the participant during the study
12. Is a family member or employee of the investigator

Primary outcomes:
measure: Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826
timeFrame: Up to 6 weeks ± 4 days post infusion with BAX826.
measure: Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments)
timeFrame: Screening (Day -30 to -2); Advate Administration (Study Day 1) pre & postdose, and Day 4; Advate washout 96 hours to 4 weeks; BAX826 Administration Day 1 pre & postdose, Post BAX826 Day 4, 8, 14, and 23; and study termination visit, week 6 ± 4 days
measure: Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII)
timeFrame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
measure: Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826)
timeFrame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
measure: Immunogenicity: Binding Antibodies to Factor VIII (FVIII)
timeFrame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
measure: Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies
timeFrame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
measure: Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies
timeFrame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
measure: Immunogenicity: Human Anti-murine Antibodies (HAMA)
timeFrame: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Secondary outcomes:
measure: Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Terminal Half-life (t1/2)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Mean Residence Time (MRT)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Total Body Clearance (CL)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Incremental Recovery (IR)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Volume of Distribution at Steady State (Vss)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Maximum Plasma Concentration (Cmax)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h)
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours.
measure: Comparison of Key Pharmacokinetic Parameters by Cohort
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.
measure: Summary of Assessment of Dose Proportionality for BAX 826
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours.
Other outcomes:
Locations:
city: Plovdiv
country: Bulgaria
facility: UMHAT "Sv. Georgi", EAD
city: Hannover
country: Germany
facility: Werlhof-Institut
state: Niedersachsen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Berlin
country: Germany
facility: Vivantes Klinikum im Friedrichshain - Landsberger Allee
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Marburg
country: Germany
facility: Universitaetsklinikum Gießen
city: Budapest
country: Hungary
facility: Semmelweis Egyetem AOK I.sz. Belgyogyaszati Klinika
city: Castelfranco Veneto
country: Italy
facility: Presidio Ospedaliero di Castelfranco Veneto
state: Treviso
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Roma
country: Italy
facility: Policlinico Umberto I di Roma-Università di Roma La Sapienza
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
city: Kirov
country: Russian Federation
facility: FSBI "Kirov SR Institute of Hematology and Blood Transfusion FMBA"
city: Moscow
country: Russian Federation
facility: FSBI "Hematological Research Center" MoH of RF
city: Samara
country: Russian Federation
facility: SBEI HPE "Samara State Medical University" of the MoH of the RF
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
state: La Coruña
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Espases
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
state: Cornwall
city: London
country: United Kingdom
facility: Royal London Hospital
state: Greater London
city: London
country: United Kingdom
facility: Royal Free Hospital
state: Greater London
city: London
country: United Kingdom
facility: St Thomas' Hospital Centre for Haemostasis & Thrombosis
state: Greater London
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
state: Greater Manchester
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: Tiede A, Allen G, Bauer A, Chowdary P, Collins P, Goldstein B, Jiang HJ, Kӧck K, Takacs I, Timofeeva M, Wolfsegger M, Srivastava S. SHP656, a polysialylated recombinant factor VIII (PSA-rFVIII): First-in-human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A. Haemophilia. 2020 Jan;26(1):47-55. doi: 10.1111/hae.13878. Epub 2019 Nov 28.