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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.

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.

Condition or disease Intervention/treatment Phase
Hemophilia B Biological: ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg Biological: BeneFIX Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 3, 2017
Actual Primary Completion Date : October 10, 2018
Actual Study Completion Date : February 22, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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
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

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
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

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
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

Experimental: Cohort 4
One subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) per day for 6 days with 240 hours of observation
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

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
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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

  2. 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.




Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03186677


Locations
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Korea, Republic of
Eulji University Hospital
Daejeon, Korea, Republic of
Pusan National Univesity Hospital
Pusan, Korea, Republic of
Yonsei University Medical Center
Seoul, Korea, Republic of
Sponsors and Collaborators
ISU Abxis Co., Ltd.
Catalyst Biosciences
Investigators
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Principal Investigator: ChurWoo You, PhD Eulji University Hospital Seo-gu
  Study Documents (Full-Text)

Documents provided by ISU Abxis Co., Ltd.:
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Responsible Party: ISU Abxis Co., Ltd.
ClinicalTrials.gov Identifier: NCT03186677    
Other Study ID Numbers: ISU304-001/CB2679d
First Posted: June 14, 2017    Key Record Dates
Results First Posted: November 10, 2020
Last Update Posted: November 10, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ISU Abxis Co., Ltd.:
ISU304
previously treated Hemophilia B patients
FIX
Factor IX
CB2679d
Dalcinonacog alfa
Additional relevant MeSH terms:
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Hemophilia A
Hemophilia B
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked