BAX 826 Dose-Escalation Safety Study

Hemophilia A Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02716194
• Other study ID #: 291501
• Secondary ID: 2015-004079-60
• Status: Completed
• Phase: Phase 1
• Start date: March 3, 2016
• Est. completion date: January 17, 2017

Study information

• Verified date: May 2021
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: January 17, 2017
• Est. primary completion date: January 17, 2017
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Biological:
• BAX 826

• Octocog alfa

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Baxalta now part of Shire

Countries where clinical trial is conducted

Bulgaria,  Germany,  Hungary,  Italy,  Netherlands,  Poland,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-8)	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.
Secondary	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.
Secondary	Pharmacokinetics: Mean Residence Time (MRT)	Mean residence time, calculated as (AUMC 0-8 / AUC 0-8) - 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.
Secondary	Pharmacokinetics: Total Body Clearance (CL)	Systemic body clearance of drug from plasma, calculated by dose (IU/kg)/AUC0-8	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Comparison of Key Pharmacokinetic Parameters by Cohort	The key pharmacokinetic parameters (Area under the concentration-time curve from 0 to infinity (AUC0-8), 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.
Secondary	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 (AUC0-8), 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.