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Dose-escalation Study to Investigate the Safety, PK, and PD of ISU304/CB2679d in Hemophilia B Patients

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ClinicalTrials.gov Identifier: NCT03186677
Recruitment Status : Completed
First Posted : June 14, 2017
Results First Posted : November 10, 2020
Last Update Posted : November 10, 2020
Sponsor:
Collaborator:
Catalyst Biosciences
Information provided by (Responsible Party):
ISU Abxis Co., Ltd.

Tracking Information
First Submitted Date  ICMJE May 30, 2017
First Posted Date  ICMJE June 14, 2017
Results First Submitted Date  ICMJE July 20, 2020
Results First Posted Date  ICMJE November 10, 2020
Last Update Posted Date November 10, 2020
Actual Study Start Date  ICMJE June 3, 2017
Actual Primary Completion Date October 10, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 18, 2020)
Number of Adverse Events (AEs) After the Administration of Investigational Products (IP) [ Time Frame: Through study completion, an average of 8 days ]
The number of reported AEs (local/systemic/other) after IP administration was calculated by cohort.
Original Primary Outcome Measures  ICMJE
 (submitted: June 13, 2017)
incidence of Adverse events (AE) after the administration of investigational products (IP) [ Time Frame: Through study completion, an average of 8 days ]
The incidence of reported AEs (local/systemic/other) after investigational product administration shall be calculated by cohort
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 18, 2020)
  • Maximum Plasma Concentration (Cmax) [ Time Frame: 0 to 72 hours for Cohorts 1 to 3, 0 to 120 hours for Cohorts 4 and 5 ]
    Cmax analysis was conducted by cohort as a Factor IX (FIX) potency percent
  • Factor IX Inhibitor [ Time Frame: At end of study visit (an average of 8 days) ]
    The presence/absence of Factor IX (FIX) neutralizing antibodies was assessed by ELISA anti-drug assay [Dalcinonacog alfa and BeneFIX) and if positive, a modified Nijmegen assay for each subject by cohort at end of study visit. Measure description: count of participants with neutralizing antibodies. Bethesda Units >0.6 indicates presence of neutralizing antibodies. 1 BU is defined as a 50% reduction in FIX activity when adding participant plasma to a standard with known FIX activity.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 13, 2017)
  • Maximum Plasma Concentration (Cmax) [ Time Frame: before the IP administration, 0, up to 120 hours ]
    Cmax analysis by cohort shall be conducted
  • Factor IX Inhibitor [ Time Frame: before the IP administration, end of study visit (an average of 8 days) ]
    The analysis of FIX inhibitors (neutralizing antibodies) shall be conducted for each subject by cohort
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose-escalation Study to Investigate the Safety, PK, and PD of ISU304/CB2679d in Hemophilia B Patients
Official Title  ICMJE A Phase 1, Open-label, Multi-center, Dose-escalation Study to Investigate the Safety, Pharmacokinetics and Pharmacodynamics of ISU304 in Previously Treated Hemophilia B Patients
Brief Summary This study is a phase 1, open-label, multi-center, dose-escalation study to investigate the safety, pharmacokinetics and pharmacodynamics of ISU304/CB2679d in previously treated hemophilia B patients.
Detailed Description

This study is a phase 1, open-label, multi-center, dose-escalation study to investigate the safety, pharmacokinetics, and pharmacodynamics of ISU304/CB2679d/Dalcinonacog alfa in previously treated Hemophilia B patients.

This study is comprised of 5 cohorts. Each cohort may receive an intravenous administration of 75 IU/kg, with subcutaneous administrations from 75 IU/kg to 150 IU/kg.

During the study period, a subject may be hospitalized to facilitate the collection of blood samples for pharmacokinetic (PK)/pharmacodynamic (PD) analysis. The Data Safety Monitoring Board (DSMB) and Data Monitoring Committee (DMC) will be operated after the end of Cohorts 1 to 4. These committees will monitor the PK/PD and safety data from each cohort to determine the continuation of next cohort (Cohorts 2 to 5), target dose, and blood sampling period for PK/PD (including timing of collection). Additional subjects may be enrolled in all cohorts or cohorts may be canceled depending on the results of PK/PD analysis. A cohort of subcutaneous dosing at 300 IU/kg was cancelled as single-dose PK is uninformative.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hemophilia B
Intervention  ICMJE
  • Biological: ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
    ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg by intravenous or subcutaneous
    Other Name: Dalcinonacog alfa
  • Biological: BeneFIX
    BeneFIX 75 IU/kg, intravenous administration
Study Arms  ICMJE
  • Experimental: Cohort 1
    Single intravenous administration of BeneFIX (75 IU/kg) with 72 hours of observation, followed by single intravenous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) with 72 hours of observation
    Interventions:
    • Biological: ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
    • Biological: BeneFIX
  • Experimental: Cohort 2
    Single intravenous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) with 72 hours of observation, followed by single subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) with 72 hours of observation
    Intervention: Biological: ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
  • Experimental: Cohort 3
    Single intravenous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) with 72 hours of observation, followed by single subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) with 120 hours of observation
    Intervention: Biological: ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
  • Experimental: Cohort 4
    One subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) per day for 6 days with 240 hours of observation
    Intervention: Biological: ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
  • Experimental: Cohort 5
    One intravenous administration of ISU304/CB2679d/Dalcinonacog alfa (75 IU/kg) followed by subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) once daily for 9 days with 312 hours of observation
    Intervention: Biological: ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 18, 2020)
11
Original Estimated Enrollment  ICMJE
 (submitted: June 13, 2017)
12
Actual Study Completion Date  ICMJE February 22, 2019
Actual Primary Completion Date October 10, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Previously treated male patients with moderate or severe hemophilia B (documented FIX activity ≤ 2% and exposed to any FIX product for ≥ 150 exposure days (estimated) at the time of screening)
  2. Patients must be 12 to 65 years old at the time of screening
  3. Patients who have discontinued a previously treated FIX product at least 4 days prior to the administration of investigational product
  4. HIV negative, or if HIV positive with a CD4 count > 200/μL (documented < 200 particles/μL or ≤ 400,000 copies/mL) at the time of screening
  5. Voluntary consent to participate in the study

Exclusion Criteria:

  1. Patients with a history or a family history of FIX inhibitors
  2. Patients with FIX inhibitors (positive result for BeneFIX or ISU304 from inhibitor tests) at the time of screening
  3. Patients who have a history of thromboembolic events (myocardial infarction, cerebrovascular disease, venous thrombosis, etc.)
  4. Patients with known hypersensitivity, allergy, or anaphylaxis to any FIX product or hamster protein
  5. Patients receiving treatment with a FIX product or a bypass agent within 4 half-lives for the agent used (at least 96 hours) prior to the administration of the investigational product
  6. Patients who have been exposed to long-term administration of immunomodulating agents or immunosuppressants such as α-INF or adrenocortical hormones over the past 3 months or who are currently receiving or planning to receive such treatment during the study period
  7. Patients who have been administered vaccines during the period of 6 months prior to the administration of the investigational product or plan to receive vaccines during the study period
  8. Patients with any other co-existing bleeding disorder (Von Willebrand disease, etc.)
  9. Patients with positive D-dimer results (≥ 0.5 μg/mL) at the time of screening
  10. Patients with platelet counts less than 100,000/μL at the time of screening
  11. Patients with ALT, AST levels 5 times greater than upper normal limit or total bilirubin, serum creatinine levels 2 times greater than upper normal limit at the time of screening
  12. Active hepatitis patients who are HBs Ag positive or anti-HCV Ab positive at the time of screening
  13. Patients scheduled for surgery during the study period
  14. Patients participated in another study within 30 days before screening or scheduled to participate in any other study during the study period
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03186677
Other Study ID Numbers  ICMJE ISU304-001/CB2679d
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party ISU Abxis Co., Ltd.
Study Sponsor  ICMJE ISU Abxis Co., Ltd.
Collaborators  ICMJE Catalyst Biosciences
Investigators  ICMJE
Principal Investigator: ChurWoo You, PhD Eulji University Hospital Seo-gu
PRS Account ISU Abxis Co., Ltd.
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP