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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.

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hemophilia B
Interventions Biological: ISU304/CB2679d/Dalcinonacog alfa 75~150 IU/kg
Biological: BeneFIX
Enrollment 11
Recruitment Details  
Pre-assignment Details There were 11 unique subjects who completed the study; 2 failed screening. Of the 5 subjects in Cohort 4, 1 subject previously participated in Cohort 1 and 2 subjects in Cohort 2. Of the 2 subjects in Cohort 5, 2 subjects previously participated in Cohort 4. As a result, the Safety Analysis Set included 16 subjects. Cohorts were conducted in numerical order.
Arm/Group Title Period 1, Cohort 1 Period 1, Cohort 2 Period 1, Cohort 3 Period 2, Cohort 4 Period 2, Cohort 5
Hide Arm/Group 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
Period Title: Period 1
Started 3 3 3 0 0
Completed 3 3 3 0 0
Not Completed 0 0 0 0 0
Period Title: Period 2
Started 0 0 0 5 2
Completed 0 0 0 5 2
Not Completed 0 0 0 0 0
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Total
Hide Arm/Group 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 Total of all reporting groups
Overall Number of Baseline Participants 3 3 3 2 0 11
Hide Baseline Analysis Population Description
There were 13 unique subjects in the study: 11 completed study and 2 failed screening. Of the 11 individuals who completed the study, 5 were in multiple cohorts. Baseline characteristics are reported according to the initial cohort to which subjects were assigned. The 2 subjects who participated in Cohort 5 were previously in Cohort 4.
Age, Categorical   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 2 participants 0 participants 11 participants
<=18 years
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
1
   9.1%
Between 18 and 65 years
2
  66.7%
3
 100.0%
3
 100.0%
2
 100.0%
0
10
  90.9%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
0
   0.0%
[1]
Measure Analysis Population Description: There were 13 unique subjects in the study; 11 completed study and 2 failed screening. Of the 11 individuals who completed the study, 5 were in multiple cohorts. 16 subjects were included in the Safety Analysis Set across 5 cohorts.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3 participants 3 participants 3 participants 2 participants 0 participants 11 participants
29.00  (16.70) 46.33  (5.69) 43.33  (14.57) 50.50  (3.87) 41.55  (13.68)
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 2 participants 0 participants 11 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
0
   0.0%
Male
3
 100.0%
3
 100.0%
3
 100.0%
2
 100.0%
0
11
 100.0%
[1]
Measure Analysis Population Description: There were 13 unique subjects in the study; 11 completed study and 2 failed screening. Of the 11 individuals who completed the study, 5 were in multiple cohorts. 16 subjects were included in the Safety Analysis Set across 5 cohorts.
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 2 participants 0 participants 11 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
0
   0.0%
Asian
3
 100.0%
3
 100.0%
3
 100.0%
2
 100.0%
0
11
 100.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
0
   0.0%
White
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
0
   0.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
South Korea Number Analyzed 3 participants 3 participants 3 participants 2 participants 0 participants 11 participants
3
 100.0%
3
 100.0%
3
 100.0%
2
 100.0%
0
11
 100.0%
1.Primary Outcome
Title Number of Adverse Events (AEs) After the Administration of Investigational Products (IP)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
There were 13 unique subjects in the study: 11 completed study and 2 failed screening. Of the 11 individuals who completed the study, 5 were in multiple cohorts. 16 subjects were included in the Safety Analysis Set across 5 cohorts.
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5
Hide Arm/Group 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
Overall Number of Participants Analyzed 3 3 3 5 2
Measure Type: Number
Unit of Measure: adverse events
0 10 10 69 47
2.Secondary Outcome
Title Maximum Plasma Concentration (Cmax)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5
Hide Arm/Group 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
Overall Number of Participants Analyzed 3 3 3 5 2
Mean (Standard Deviation)
Unit of Measure: FIX potency percent
Cmax of ISU304/CB2679d/Dalcinonacog alfa IV 71.10  (15.87) 100.80  (78.00) 41.70  (7.47) 15.34  (2.44) 23.80  (10.04)
Cmax of ISU304/CB2679d/Dalcinonacog alfa SC 70.47  (16.92) 5.30  (3.69) 5.27  (1.16) NA [1]   (NA) NA [1]   (NA)
[1]
Cmax calculated for only one treatment and route of administration (subcutaneous) in this cohort.
3.Secondary Outcome
Title Factor IX Inhibitor
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5
Hide Arm/Group 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
Overall Number of Participants Analyzed 3 3 3 5 2
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
 100.0%
Time Frame For 7 to 15 days depending on the cohort: Cohort 1 (7 days), Cohort 2 (7 days), Cohort 3 (9 days), Cohort 4 (10 days), Cohort 5 (15 days)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5
Hide Arm/Group 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 subcutaneous administration of ISU304/CB2679d/Dalcinonacog alfa (150 IU/kg) once daily for 9 days with 312 hours of observation
All-Cause Mortality
Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/3 (0.00%)      0/3 (0.00%)      0/3 (0.00%)      0/5 (0.00%)      0/2 (0.00%)    
Hide Serious Adverse Events
Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/3 (0.00%)      0/3 (0.00%)      0/3 (0.00%)      0/5 (0.00%)      0/2 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/3 (0.00%)      3/3 (100.00%)      3/3 (100.00%)      5/5 (100.00%)      2/2 (100.00%)    
Gastrointestinal disorders           
Diarrhea  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/5 (20.00%)  1 0/2 (0.00%)  0
General disorders           
Injection site pain  1  0/3 (0.00%)  0 2/3 (66.67%)  2 3/3 (100.00%)  3 5/5 (100.00%)  34 2/2 (100.00%)  11
Injection site erythema  1  0/3 (0.00%)  0 1/3 (33.33%)  2 3/3 (100.00%)  3 2/5 (40.00%)  32 2/2 (100.00%)  15
Injection site papule  1  0/3 (0.00%)  0 0/3 (0.00%)  0 2/3 (66.67%)  2 0/5 (0.00%)  0 2/2 (100.00%)  9
Injection site pruritus  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/5 (0.00%)  0 1/2 (50.00%)  2
Injection site discomfort  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/5 (0.00%)  0 0/2 (0.00%)  0
Pain  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/5 (0.00%)  0 0/2 (0.00%)  0
Investigations           
Anti ISU304 antibody positive  1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/5 (0.00%)  0 2/2 (100.00%)  2
Metabolism and nutrition disorders           
Decreased appetite  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/5 (0.00%)  0 2/2 (100.00%)  2
Musculoskeletal and connective tissue disorders           
Musculoskeletal stiffness  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/5 (0.00%)  0 1/2 (50.00%)  1
Skin and subcutaneous tissue disorders           
Erythema  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/5 (0.00%)  0 1/2 (50.00%)  1
Pruritus  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/5 (0.00%)  0 1/2 (50.00%)  2
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Two subjects who were cousins developed neutralizing antibodies to dalcinonacog alfa in Cohort 5 that did not cross react with wild-type FIX. Both resumed their prior FIX therapy. Five subjects participated in 2 cohorts each.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Howard Levy, Chief Medical Officer
Organization: Catalyst Biosciences
Phone: +1.650.266.6871
EMail: hlevy@catbio.com
Layout table for additonal information
Responsible Party: ISU Abxis Co., Ltd.
ClinicalTrials.gov Identifier: NCT03186677    
Other Study ID Numbers: ISU304-001/CB2679d
First Submitted: May 30, 2017
First Posted: June 14, 2017
Results First Submitted: July 20, 2020
Results First Posted: November 10, 2020
Last Update Posted: November 10, 2020