BAX 826 Dose-Escalation Safety Study

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

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)

Study Overview

• Status: Completed
• Conditions: Hemophilia A
• Intervention / Treatment: Biological: BAX 826; Biological: Octocog alfa

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • UMHAT "Sv. Georgi", EAD
• Germany
  • Berlin, Germany, 10249
    • Vivantes Klinikum im Friedrichshain - Landsberger Allee
  • Homburg, Germany, 66421
    • Universitaetsklinikum des Saarlandes
  • Marburg, Germany, 35043
    • Universitaetsklinikum Giessen
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover
    • Hannover, Niedersachsen, Germany, 30159
      • Werlhof-Institut
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem AOK I.sz. Belgyogyaszati Klinika
• Italy
  • Milano, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Roma, Italy, 00144
    • Policlinico Umberto I di Roma-Università di Roma La Sapienza
  • Treviso
    • Castelfranco Veneto, Treviso, Italy, 31033
      • Presidio Ospedaliero di Castelfranco Veneto
• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • Radboud University Nijmegen Medical Centre
  • Rotterdam, Netherlands, 3015 AA
    • Erasmus Medisch Centrum
• Poland
  • Warszawa, Poland, 02-776
    • Instytut Hematologii i Transfuzjologii
• Russian Federation
  • Kirov, Russian Federation, 610027
    • FSBI "Kirov SR Institute of Hematology and Blood Transfusion FMBA"
  • Moscow, Russian Federation, 125167
    • FSBI "Hematological Research Center" MoH of RF
  • Samara, Russian Federation, 443099
    • SBEI HPE "Samara State Medical University" of the MoH of the RF
• Spain
  • Alicante, Spain, 03010
    • Hospital General Universitario de Alicante
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Malaga, Spain, 29010
    • Hospital Regional Universitario de Malaga
  • Palma de Mallorca, Spain, 07120
    • Hospital Universitario Son Espases
  • La Coruña
    • A Coruña, La Coruña, Spain, 15006
      • Complejo Hospitalario Universitario A Coruña
• United Kingdom
  • Cornwall
    • Truro, Cornwall, United Kingdom, TR1 3LJ
      • Royal Cornwall Hospital
  • Greater London
    • London, Greater London, United Kingdom, NW3 2QG
      • Royal Free Hospital
    • London, Greater London, United Kingdom, E1 1BB
      • Royal London Hospital
    • London, Greater London, United Kingdom, SE1 7EH
      • St Thomas' Hospital Centre for Haemostasis & Thrombosis
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M13 9WL
      • Manchester Royal Infirmary
  • West Glamorgan
    • Cardiff, West Glamorgan, United Kingdom, CF14 4XW
      • University Hospital of Wales

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 - Low dose; The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level.	Biological: BAX 826; Other Names: BAX826; Biological: Octocog alfa; Other Names: ADVATE; ADVATE (Antihemophilic Factor [Recombinant])
Experimental: Cohort 2 - Medium dose; The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level.	Biological: BAX 826; Other Names: BAX826; Biological: Octocog alfa; Other Names: ADVATE; ADVATE (Antihemophilic Factor [Recombinant])
Experimental: Cohort 3 - High dose; The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level.	Biological: BAX 826; Other Names: BAX826; Biological: Octocog alfa; Other Names: ADVATE; ADVATE (Antihemophilic Factor [Recombinant])

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826	Serious Adverse Events and non-serious Adverse Events the occurred after infusion with BAX 826.	Up to 6 weeks ± 4 days post infusion with BAX826.
Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments)	Clinically significant results after treatment with investigational product that constitute an AE are counted. Vital signs include body temperature, respiratory rate, pulse rate, and blood pressure. Clinical laboratory results include: Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (i.e. basophils, eosinophils, lymphocytes, monocytes and neutrophils), international normalized ratio (INR), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet count. Clinical Chemistry: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, glucose. Lipid panel: cholesterol, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides	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
Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII)	Inhibition of FVIII activity by antibodies binding to FVIII were measured using the Nijmegen modification of the Bethesda inhibitor assay.	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
Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826)	Binding antibodies to PSA FVIII (ie BAX 826) IgG and IgM	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
Immunogenicity: Binding Antibodies to Factor VIII (FVIII)	Binding antibodies to FVIII IgG and IgM	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
Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies	Binding antibodies to PSA (IgG and IgM)	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
Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies	Binding antibodies to CHO	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
Immunogenicity: Human Anti-murine Antibodies (HAMA)	Binding antibodies HAMA (IgG)	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞)	Area under the FVIII activity-time curve from zero extrapolated to infinity, calculated by linear-up/log-down trapezoidal method and extrapolated to infinity, calculated as AUC last + C last / lambda z, where Clast is the estimated concentration at the last quantifiable time point	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.
Pharmacokinetics: Terminal Half-life (t1/2)	Terminal elimination phase half-life, calculated by (ln2)/lambda z, where lambda z is the terminal rate constant, determined by linear regression of the terminal points of the log-linear FVIII activity-time curve.	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.
Pharmacokinetics: Mean Residence Time (MRT)	Mean residence time, calculated as (AUMC 0-∞ / AUC 0-∞) - TI / 2, where TI is the time duration of infusion	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.
Pharmacokinetics: Total Body Clearance (CL)	Systemic body clearance of drug from plasma, calculated by dose (IU/kg)/AUC0-∞	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.
Pharmacokinetics: Incremental Recovery (IR)	Incremental recovery (IR) at Cmax, calculated as IR = (Cmax - Cpreinfusion) / Dose (IU/kg)	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.
Pharmacokinetics: Volume of Distribution at Steady State (Vss)	Volume of distribution at steady state is calculated by MRT*CL MRT=Mean residence time CL=Clearance rate	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.
Pharmacokinetics: Maximum Plasma Concentration (Cmax)	Maximum observed FVIII activity, obtained directly from FVIII activity versus time data	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.
Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax)	Time of maximum FVIII activity is obtained directly from FVIII activity versus time data	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.
Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last)	Area under the FVIII activity-time curve from zero to the last quantifiable FVIII activity, calculated by linear-up/log-down trapezoidal method.	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.
Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h)	AUC from time zero to exactly 72 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 72 hours is missing, the activity at 72 hours will be interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z).	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.
Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826	AUC from time zero to exactly 168 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 168 hours is missing, the activity at 168 hours was interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z). This parameter will be calculated for BAX 826 only.	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.
Comparison of Key Pharmacokinetic Parameters by Cohort	The key pharmacokinetic parameters (Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from 0 to 72 hours (AUC0-72h), Maximum plasma concentration (Cmax), Terminal half-life (t1/2), Mean residence time (MRT) and Total body clearance (CL)) for ADVATE and BAX 826 have been compared.	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.
Summary of Assessment of Dose Proportionality for BAX 826	Dose Proportionality for BAX 826 was calculated for the parameters Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from time 0 to the last quantifiable time point (AUC0-last) and Maximum plasma concentration (Cmax).	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.

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2016
• Primary Completion (Actual): January 17, 2017
• Study Completion (Actual): January 17, 2017

Study Registration Dates

• First Submitted: March 17, 2016
• First Submitted That Met QC Criteria: March 17, 2016
• First Posted (Estimate): March 23, 2016

Study Record Updates

• Last Update Posted (Actual): May 25, 2021
• Last Update Submitted That Met QC Criteria: May 3, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: 291501; 2015-004079-60 (EudraCT Number)