BAX 826 Dose-Escalation Safety Study

Phase 1

Completed

Conditions: Hemophilia A

Interventions: Biological: BAX 826
Biological: Octocog alfa

Registration Number: NCT02716194

Lead Sponsor: Baxalta now part of Shire

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)

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 40

Inclusion Criteria

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

Exclusion Criteria

Detectable FVIII inhibitor at screening, with a titer ≥0.6 Bethesda Unit (BU)
Documented history of FVIII inhibitors with a titer ≥0.4 BU at any time prior to screening
Known clinical hypersensitivity towards mouse or hamster proteins or to polysialic acid (PSA)
Scheduled elective surgery during study participation
Severe chronic hepatic dysfunction
Severe renal impairment
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
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
Diagnosis of an inherited or acquired hemostatic defect other than hemophilia A
Currently receiving, or scheduled to receive during the course of the study, an immune-modulating drug other than antiretroviral chemotherapy
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
Is a family member or employee of the investigator

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Cohort 3 - High dose	BAX 826	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.
Cohort 1 - Low dose	Octocog alfa	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.
Cohort 2 - Medium dose	BAX 826	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.
Cohort 2 - Medium dose	Octocog alfa	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.
Cohort 1 - Low dose	BAX 826	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.
Cohort 3 - High dose	Octocog alfa	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.

Primary Outcome Measures

Name	Time	Method
Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826	Up to 6 weeks ± 4 days post infusion with BAX826.	Serious Adverse Events and non-serious Adverse Events the occurred after infusion with BAX 826.
Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments)	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	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
Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII)	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	Inhibition of FVIII activity by antibodies binding to FVIII were measured using the Nijmegen modification of the Bethesda inhibitor assay.
Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826)	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	Binding antibodies to PSA FVIII (ie BAX 826) IgG and IgM
Immunogenicity: Binding Antibodies to Factor VIII (FVIII)	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	Binding antibodies to FVIII IgG and IgM
Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies	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	Binding antibodies to PSA (IgG and IgM)
Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies	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	Binding antibodies to CHO
Immunogenicity: Human Anti-murine Antibodies (HAMA)	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	Binding antibodies HAMA (IgG)

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (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.	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
Pharmacokinetics: Terminal Half-life (t1/2)	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.	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.
Pharmacokinetics: Mean Residence Time (MRT)	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.	Mean residence time, calculated as (AUMC 0-∞ / AUC 0-∞) - TI / 2, where TI is the time duration of infusion
Pharmacokinetics: Total Body Clearance (CL)	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.	Systemic body clearance of drug from plasma, calculated by dose (IU/kg)/AUC0-∞
Pharmacokinetics: Incremental Recovery (IR)	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.	Incremental recovery (IR) at Cmax, calculated as IR = (Cmax - Cpreinfusion) / Dose (IU/kg)
Pharmacokinetics: Volume of Distribution at Steady State (Vss)	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.	Volume of distribution at steady state is calculated by MRT\*CL MRT=Mean residence time CL=Clearance rate
Pharmacokinetics: 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, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.	Maximum observed FVIII activity, obtained directly from FVIII activity versus time data
Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax)	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.	Time of maximum FVIII activity is obtained directly from FVIII activity versus time data
Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last)	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.	Area under the FVIII activity-time curve from zero to the last quantifiable FVIII activity, calculated by linear-up/log-down trapezoidal method.
Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h)	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.	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).
Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826	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.	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.
Comparison of Key Pharmacokinetic Parameters by Cohort	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.	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.
Summary of Assessment of Dose Proportionality for BAX 826	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.	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).

Trial Locations

Locations (28): SBEI HPE "Samara State Medical University" of the MoH of the RF
🇷🇺
Samara, Russian Federation
Royal Cornwall Hospital
🇬🇧
Truro, Cornwall, United Kingdom
FSBI "Hematological Research Center" MoH of RF
🇷🇺
Moscow, Russian Federation
Radboud University Nijmegen Medical Centre
🇳🇱
Nijmegen, Netherlands
Erasmus Medisch Centrum
🇳🇱
Rotterdam, Netherlands
Instytut Hematologii i Transfuzjologii
🇵🇱
Warszawa, Poland
Presidio Ospedaliero di Castelfranco Veneto
🇮🇹
Castelfranco Veneto, Treviso, Italy
Semmelweis Egyetem AOK I.sz. Belgyogyaszati Klinika
🇭🇺
Budapest, Hungary
Werlhof-Institut
🇩🇪
Hannover, Niedersachsen, Germany
Medizinische Hochschule Hannover
🇩🇪
Hannover, Niedersachsen, Germany
Vivantes Klinikum im Friedrichshain - Landsberger Allee
🇩🇪
Berlin, Germany
Universitaetsklinikum des Saarlandes
🇩🇪
Homburg, Germany
Universitaetsklinikum Gießen
🇩🇪
Marburg, Germany
Policlinico Umberto I di Roma-Università di Roma La Sapienza
🇮🇹
Roma, Italy
FSBI "Kirov SR Institute of Hematology and Blood Transfusion FMBA"
🇷🇺
Kirov, Russian Federation
Complejo Hospitalario Universitario A Coruña
🇪🇸
A Coruña, La Coruña, Spain
Hospital General Universitario de Alicante
🇪🇸
Alicante, Spain
Hospital Universitari Vall d'Hebron
🇪🇸
Barcelona, Spain
Hospital Regional Universitario de Malaga
🇪🇸
Malaga, Spain
Hospital Universitario Son Espases
🇪🇸
Palma de Mallorca, Spain
Hospital Universitario La Paz
🇪🇸
Madrid, Spain
St Thomas' Hospital Centre for Haemostasis & Thrombosis
🇬🇧
London, Greater London, United Kingdom
Manchester Royal Infirmary
🇬🇧
Manchester, Greater Manchester, United Kingdom
Royal London Hospital
🇬🇧
London, Greater London, United Kingdom
Royal Free Hospital
🇬🇧
London, Greater London, United Kingdom
University Hospital of Wales
🇬🇧
Cardiff, West Glamorgan, United Kingdom
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
🇮🇹
Milano, Italy
UMHAT "Sv. Georgi", EAD
🇧🇬
Plovdiv, Bulgaria