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

Study Description

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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; 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 in previously treated hemophilia B patients.

This study is comprised of 5 cohorts. Each cohort will receive an identical intravenous administration of 75 IU/kg, with subcutaneous administrations doubling from 75 IU/kg until 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	12 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
Estimated Primary Completion Date :	October 30, 2018
Estimated Study Completion Date :	October 30, 2018

Arms and Interventions

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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 (75 IU/kg) with 72 hours of observation	Biological: ISU304/CB2679d; ISU304/CB2679d 75~150 IU/kg by intravenous or subcutaneous; Biological: BeneFix; BeneFIX 75 IU/kg, intravenous administration
Experimental: Cohort 2; Single intravenous administration of ISU304/CB2679d (75 IU/kg) with 72 hours of observation, followed by single subcutaneous administration of ISU304/CB2679d (75 IU/kg) with 72 hours of observation	Biological: ISU304/CB2679d; ISU304/CB2679d 75~150 IU/kg by intravenous or subcutaneous
Experimental: Cohort 3; Single intravenous administration of ISU304/CB2679d (75 IU/kg) with 72 hours of observation, followed by single subcutaneous administration of ISU304/CB2679d (150 IU/kg) with 120 hours of observation	Biological: ISU304/CB2679d; ISU304/CB2679d 75~150 IU/kg by intravenous or subcutaneous
Experimental: Cohort 4; One subcutaneous administration of ISU304/CB2679d (300 IU/kg) per day for 6 days with 144 hours of observation	Biological: ISU304/CB2679d; ISU304/CB2679d 75~150 IU/kg by intravenous or subcutaneous
Experimental: Cohort 5; One intravenous administration of ISU304/CB2679d (75 IU/kg) followed subcutaneous administration of ISU304/CB2679d (150 IU/kg) once daily for 9 days with 312 hours of observation	Biological: ISU304/CB2679d; ISU304/CB2679d 75~150 IU/kg by intravenous or subcutaneous

Outcome Measures

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Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. Maximum Plasma Concentration (Cmax) [ Time Frame: before the IP administration, 0, up to 120 hours ]
   Cmax analysis by cohort shall be conducted
2. 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

Eligibility Criteria

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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 mg/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

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Contacts

Contact: Suyeong Kim, MPharm	+82 31 696 4621	andante4me@isu.co.kr

Locations

Korea, Republic of
Eulji University Hospital	Recruiting
Daejeon, Korea, Republic of
Contact: Chur Woo You, Dr.
Pusan National Univesity Hospital	Recruiting
Pusan, Korea, Republic of
Contact: Ho-Jin Shin, Dr.
Yonsei University Medical Center	Recruiting
Seoul, Korea, Republic of
Contact: Jin Seok Kim, Dr.

Sponsors and Collaborators

ISU Abxis Co., Ltd.

Catalyst Biosciences

Investigators

Study Director:	Jaehyeon Juhn, Ph.D	ISU Abxis Co., Ltd.

More Information

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Responsible Party:	ISU Abxis Co., Ltd.
ClinicalTrials.gov Identifier:	NCT03186677 History of Changes
Other Study ID Numbers:	ISU304-001/CB2679d
First Posted:	June 14, 2017
Last Update Posted:	July 19, 2018
Last Verified:	July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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

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