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

• 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: ISU Abxis Co., Ltd.
• Collaborator: Catalyst Biosciences
• Information provided by (Responsible Party): ISU Abxis Co., Ltd.

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.

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Locations

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

• Principal Investigator: ChurWoo You, PhD; Eulji University Hospital Seo-gu

  Study Documents (Full-Text)

Documents provided by ISU Abxis Co., Ltd.:

Study Protocol and Statistical Analysis Plan  [PDF] September 11, 2018

More Information

• Responsible Party: ISU Abxis Co., Ltd.
• ClinicalTrials.gov Identifier: NCT03186677
• Other Study ID Numbers: ISU304-001/CB2679d
• First Posted: June 14, 2017
• 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

• 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:

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