BAX 826 Dose-Escalation Safety Study

NCT02716194 | Completed Phase 1 Results

• 2 other identifiers: 2915012015-004079-60
• Study Type: interventional
• Target: 40
• Locations: 9 countries
• Sites: 28

Brief Summary

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

Conditions

Hemophilia A

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (13)

• 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.

• 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.

• 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.

• 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.

• 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.

Study Arms (3)

Cohort 1 - Low dose

EXPERIMENTAL

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; Biological: Octocog alfa

Cohort 2 - Medium dose

EXPERIMENTAL

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; Biological: Octocog alfa

Cohort 3 - High dose

EXPERIMENTAL

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; Biological: Octocog alfa

Interventions

BAX 826 BIOLOGICAL

Also known as: BAX826

Cohort 1 - Low dose; Cohort 2 - Medium dose; Cohort 3 - High dose

Octocog alfa BIOLOGICAL

Also known as: ADVATE (Antihemophilic Factor [Recombinant]), ADVATE

Cohort 1 - Low dose; Cohort 2 - Medium dose; Cohort 3 - High dose

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Baxalta now part of Shire: lead

Study Sites (28)

UMHAT "Sv. Georgi", EAD

Plovdiv, 4000, Bulgaria

Location

Werlhof-Institut

Hanover, Lower Saxony, 30159, Germany

Location

Medizinische Hochschule Hannover

Hanover, Lower Saxony, 30625, Germany

Location

Vivantes Klinikum im Friedrichshain - Landsberger Allee

Berlin, 10249, Germany

Location

Universitaetsklinikum des Saarlandes

Homburg, 66421, Germany

Location

Universitaetsklinikum Gießen

Marburg, 35043, Germany

Location

Semmelweis Egyetem AOK I.sz. Belgyogyaszati Klinika

Budapest, 1083, Hungary

Location

Presidio Ospedaliero di Castelfranco Veneto

Castelfranco Veneto, Treviso, 31033, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

Policlinico Umberto I di Roma-Università di Roma La Sapienza

Roma, 00144, Italy

Location

Radboud University Nijmegen Medical Centre

Nijmegen, 6525 GA, Netherlands

Location

Erasmus Medisch Centrum

Rotterdam, 3015 AA, Netherlands

Location

Instytut Hematologii i Transfuzjologii

Warsaw, 02-776, Poland

Location

FSBI "Kirov SR Institute of Hematology and Blood Transfusion FMBA"

Kirov, 610027, Russia

Location

FSBI "Hematological Research Center" MoH of RF

Moscow, 125167, Russia

Location

SBEI HPE "Samara State Medical University" of the MoH of the RF

Samara, 443099, Russia

Location

Complejo Hospitalario Universitario A Coruña

A Coruña, La Coruña, 15006, Spain

Location

Hospital General Universitario de Alicante

Alicante, 03010, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Regional Universitario de Malaga

Málaga, 29010, Spain

Location

Hospital Universitario Son Espases

Palma de Mallorca, 07120, Spain

Location

Royal Cornwall Hospital

Truro, Cornwall, TR1 3LJ, United Kingdom

Location

Royal London Hospital

London, Greater London, E1 1BB, United Kingdom

Location

Royal Free Hospital

London, Greater London, NW3 2QG, United Kingdom

Location

St Thomas' Hospital Centre for Haemostasis & Thrombosis

London, Greater London, SE1 7EH, United Kingdom

Location

Manchester Royal Infirmary

Manchester, Greater Manchester, M13 9WL, United Kingdom

Location

University Hospital of Wales

Cardiff, West Glamorgan, CF14 4XW, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 31778283 DERIVED

MeSH Terms

Conditions

Hemophilia A

Interventions

F8 protein, human; Factor VIII

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Results Point of Contact

• Title: Study Director
• Organization: Shire

ClinicalTransparency@shire.com

+1 866 842 5335

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 17, 2016
• First Posted: March 23, 2016
• Study Start: March 3, 2016
• Primary Completion: January 17, 2017
• Study Completion: January 17, 2017
• Last Updated: May 25, 2021
• Results First Posted: September 20, 2018

Record last verified: 2021-05

Locations

IT (3); HU (1); RU (3); ES (6); BU (1); NL (2); DE (5); PL (1); GB (6)