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

Primary Purpose

Hemophilia B

Status
Completed
Phase
Phase 1
Locations
Korea, Republic of
Study Type
Interventional
Intervention
ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
BeneFIX
Sponsored by
ISU Abxis Co., Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia B focused on measuring ISU304, previously treated Hemophilia B patients, FIX, Factor IX, CB2679d, Dalcinonacog alfa

Eligibility Criteria

12 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Eulji University Hospital
  • Pusan National Univesity Hospital
  • Yonsei University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Cohort 5

Arm Description

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

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

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

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

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

Outcomes

Primary Outcome Measures

Number of Adverse Events (AEs) After the Administration of Investigational Products (IP)
The number of reported AEs (local/systemic/other) after IP administration was calculated by cohort.

Secondary Outcome Measures

Maximum Plasma Concentration (Cmax)
Cmax analysis was conducted by cohort as a Factor IX (FIX) potency percent
Factor IX Inhibitor
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.

Full Information

First Posted
May 30, 2017
Last Updated
October 18, 2020
Sponsor
ISU Abxis Co., Ltd.
Collaborators
Catalyst Biosciences
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1. Study Identification

Unique Protocol Identification Number
NCT03186677
Brief Title
Dose-escalation Study to Investigate the Safety, PK, and PD of ISU304/CB2679d in Hemophilia B Patients
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
June 3, 2017 (Actual)
Primary Completion Date
October 10, 2018 (Actual)
Study Completion Date
February 22, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ISU Abxis Co., Ltd.
Collaborators
Catalyst Biosciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia B
Keywords
ISU304, previously treated Hemophilia B patients, FIX, Factor IX, CB2679d, Dalcinonacog alfa

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 4
Arm Type
Experimental
Arm Description
One subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) per day for 6 days with 240 hours of observation
Arm Title
Cohort 5
Arm Type
Experimental
Arm Description
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 Type
Biological
Intervention Name(s)
ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
Other Intervention Name(s)
Dalcinonacog alfa
Intervention Description
ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg by intravenous or subcutaneous
Intervention Type
Biological
Intervention Name(s)
BeneFIX
Intervention Description
BeneFIX 75 IU/kg, intravenous administration
Primary Outcome Measure Information:
Title
Number of Adverse Events (AEs) After the Administration of Investigational Products (IP)
Description
The number of reported AEs (local/systemic/other) after IP administration was calculated by cohort.
Time Frame
Through study completion, an average of 8 days
Secondary Outcome Measure Information:
Title
Maximum Plasma Concentration (Cmax)
Description
Cmax analysis was conducted by cohort as a Factor IX (FIX) potency percent
Time Frame
0 to 72 hours for Cohorts 1 to 3, 0 to 120 hours for Cohorts 4 and 5
Title
Factor IX Inhibitor
Description
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.
Time Frame
At end of study visit (an average of 8 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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) Patients must be 12 to 65 years old at the time of screening Patients who have discontinued a previously treated FIX product at least 4 days prior to the administration of investigational product 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 Voluntary consent to participate in the study Exclusion Criteria: Patients with a history or a family history of FIX inhibitors Patients with FIX inhibitors (positive result for BeneFIX or ISU304 from inhibitor tests) at the time of screening Patients who have a history of thromboembolic events (myocardial infarction, cerebrovascular disease, venous thrombosis, etc.) Patients with known hypersensitivity, allergy, or anaphylaxis to any FIX product or hamster protein 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 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 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 Patients with any other co-existing bleeding disorder (Von Willebrand disease, etc.) Patients with positive D-dimer results (≥ 0.5 μg/mL) at the time of screening Patients with platelet counts less than 100,000/μL at the time of screening 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 Active hepatitis patients who are HBs Ag positive or anti-HCV Ab positive at the time of screening Patients scheduled for surgery during the study period Patients participated in another study within 30 days before screening or scheduled to participate in any other study during the study period
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
ChurWoo You, PhD
Organizational Affiliation
Eulji University Hospital Seo-gu
Official's Role
Principal Investigator
Facility Information:
Facility Name
Eulji University Hospital
City
Daejeon
Country
Korea, Republic of
Facility Name
Pusan National Univesity Hospital
City
Pusan
Country
Korea, Republic of
Facility Name
Yonsei University Medical Center
City
Seoul
Country
Korea, Republic of

12. IPD Sharing Statement

Plan to Share IPD
No

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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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