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Phase 2b, single-center, open-label study designed to evaluate the pharmacokinetics, pharmacodynamics, efficacy and safety of subcutaneous (SC) prophylaxis treatment regimens with CB2679d in 6 adult, male subjects with severe congenital hemophilia B.
Single-center, open-label Phase 2b study will evaluate the PK, PD, efficacy and safety parameters of SC prophylaxis treatment regimens with CB2679d in adult subjects with hemophilia B. The study will enroll and dose subcutaneously, a total of 6 adult male subjects with severe congenital hemophilia B.
During the Treatment Period, the subject will receive an IV dose of 50 IU/kg followed 35 ± 5 minutes later by a SC dose of 100 IU/kg. Daily SC doses of 100 IU/kg will be administered until Day 28 (28 total SC doses). On Day 1, PK, PD, and safety assessments will be done at pre-IV dose and repeated 35 (± 5) minutes later prior to the SC dose. Subsequent PK, PD and safety assessments will be performed pre-dose on days 2, 3, 7, 14, 21 and 28.
During the Washout Period, PK, PD, and safety assessments will be done on Days 29, 30, 31, 32 and 33. Daily FIX activity levels will be measured, unless FIX activity level is known to be < 5%, as measured by local laboratory.
An End of Study visit will occur 30 days (± 2 days) after the last dose of study drug.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intravenous Dose | Experimental | Coagulation Factor IX variant, 50 IU/kg by intravenous route |
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| Subcutaneous Dosing | Experimental | Coagulation Factor IX variant, 100 IU/kg by subcutaneous route |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Coagulation Factor IX variant | Biological | Single intravenous injection of CB2679d/Dalcinonacog alfa |
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| Measure | Description | Time Frame |
|---|---|---|
| Number of Subjects Who Achieved FIX Level ≥12% | Subjects who achieved a FIX activity level ≥12% during the treatment period in the PK Population | Days 7, 14, 21, 28, 29 |
| Measure | Description | Time Frame |
|---|---|---|
| FIX Activity Levels (Actual and Change From Baseline) in All Subjects | FIX Activity Levels measured by percent activity. Baseline was defined as the lowest assessment before the first administration of study drug. Maximum change from baseline was calculated as the maximum of the changes from baseline over all visits during treatment period. FIX activity level below the limit of quantification (BLQ) were set to zero. In case of retest, the average of the different test results were considered for the summary analyses. 1 subject received a higher IV dose than allowed per protocol (150 IU/kg) at Day 1 thus this subject's values at Day 1 (SC Dose), Day 2, & Day 3 were excluded from this analysis & the total number of participants was lowered by 1 at these timepoints. Additionally, mean (standard deviation) for the maximum change from baseline in the FIX activity level (%) during SC dosing was calculated by excluding actual values at Day 1 IV dose, Day 1 SC dose, Day 2 & Day 3 for all 6 subjects. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Howard Levy, MD, PhD, MMM | Catalyst Biosciences | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Haemophilia Comprehensive Care Centre | Johannesburg | South Africa |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37341915 | Derived | Faraj A, Le Moan N, Gorina E, Blouse GE, Knudsen T, Simonsson USH. Model-Informed Support of Dose Selection for Prophylactic Treatment with Dalcinonacog Alfa in Adult and Paediatric Hemophilia B Patients. Adv Ther. 2023 Sep;40(9):3739-3750. doi: 10.1007/s12325-023-02570-6. Epub 2023 Jun 21. |
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This is a single-center, open label study so the investigator will have full access to all study subject data.
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11 subjects were screened in the study, but 4 subjects failed screening due to inclusion/exclusion criteria not met and 1 subject was screened, but withdrew consent before receiving any study medication. These 5 subjects were considered not enrolled into the Treatment Period, and the remaining 6 were considered enrolled into the Treatment Period. Of those 6 enrolled into the Treatment Period, 5 subjects completed the study. The 6 subjects enrolled comprise the Overall Subjects/Population.
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| ID | Title | Description |
|---|---|---|
| FG000 | Overall Subjects | Subjects were dosed with a single intravenous injection dose of 50 IU/kg coagulation Factor IX variant (CB2679d/Dalcinonacog alfa) and then daily subcutaneous doses of 100 IU/kg coagulation Factor IX variant (CB2679d/Dalcinonacog alfa) for 28 days |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Overall Subjects | All subjects in the Safety Population received study treatment |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Subjects Who Achieved FIX Level ≥12% | Subjects who achieved a FIX activity level ≥12% during the treatment period in the PK Population | PK population. One subject not included in the PK population discontinued the study on Day 7 and had an activity level >12% | Posted | Count of Participants | Participants | Days 7, 14, 21, 28, 29 |
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TEAEs were defined as AEs that occurred on or after the first dose of study medication or worsened after the first dose of study drug in this study but not later than the date of last dose (+30 days).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Overall Subjects | All subjects in the Safety Population received study treatment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Injection Site Reaction | General disorders | MedDRA Version 20.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Howard Levy, Chief Medical Officer | Catalyst Biosciences | +1.650.266.6871 | hlevy@catbio.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 17, 2018 | Mar 9, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 14, 2020 | Mar 9, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D002836 | Hemophilia B |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| Coagulation Factor IX variant | Biological | Daily subcutaneous injections of CB2679d/Dalcinonacog alfa for 28 days |
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| Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
| Pharmacokinetic (PK) Analysis - AUC | Summary of Pharmacokinetic Parameters - AUC Infinity Observation and AUC to Last Non-zero Concentration | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
| PK Analysis - Clearance | Summary of PK Parameters - Clearance | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
| PK Analysis - Maximum Concentration During SC Dosing | Summary of PK Parameters - Maximum Concentration during SC dosing | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
| PK Analysis - Half-Life and Residence Time | Summary of PK Parameters - Half-Life-1(alpha), Half-Life-1(beta), and Mean Residence Time | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
| PK Analysis - Volume of Distribution at Steady-State Observed | Summary of PK Parameters - Volume of Distribution at Steady-State Observed | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
| Occurrence of Clinical Thrombotic Event | Rate of occurrence of clinical thrombotic event not attributable to another cause | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28 |
| Occurrence of an Antibody Response | Rate of occurrence of an antibody response to CB2679d and cross-reactive with wild-type recombinant coagulation FIX | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28 |
| Thrombogenicity Assessment - Fibrinogen | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
| Thrombogenicity Assessment - D-Dimer | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
| Thrombogenicity Assessment - Prothrombin Fragments 1 + 2 | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
| Thrombogenicity Assessment - Thrombin/Antithrombin | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Secondary | FIX Activity Levels (Actual and Change From Baseline) in All Subjects | FIX Activity Levels measured by percent activity. Baseline was defined as the lowest assessment before the first administration of study drug. Maximum change from baseline was calculated as the maximum of the changes from baseline over all visits during treatment period. FIX activity level below the limit of quantification (BLQ) were set to zero. In case of retest, the average of the different test results were considered for the summary analyses. 1 subject received a higher IV dose than allowed per protocol (150 IU/kg) at Day 1 thus this subject's values at Day 1 (SC Dose), Day 2, & Day 3 were excluded from this analysis & the total number of participants was lowered by 1 at these timepoints. Additionally, mean (standard deviation) for the maximum change from baseline in the FIX activity level (%) during SC dosing was calculated by excluding actual values at Day 1 IV dose, Day 1 SC dose, Day 2 & Day 3 for all 6 subjects. | PK Population. 1 subject received a higher IV dose than allowed per protocol (150 IU/kg) at Day 1 thus this subject's values at Day 1 (SC Dose), Day 2, & Day 3 were excluded from this analysis & the total number of participants was lowered by 1 at these timepoints. Additionally, mean (standard deviation) for the maximum change from baseline in the FIX activity level (%) during SC dosing was calculated by excluding actual values at Day 1 IV dose, Day 1 SC dose, Day 2 & Day 3 for all 6 subjects. | Posted | Mean | Standard Deviation | % (percent) activity | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
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| Secondary | Pharmacokinetic (PK) Analysis - AUC | Summary of Pharmacokinetic Parameters - AUC Infinity Observation and AUC to Last Non-zero Concentration | PK Population | Posted | Mean | Standard Deviation | IU/dL*day | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
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| Secondary | PK Analysis - Clearance | Summary of PK Parameters - Clearance | PK Population | Posted | Mean | Standard Deviation | dL/day/kg | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
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| Secondary | PK Analysis - Maximum Concentration During SC Dosing | Summary of PK Parameters - Maximum Concentration during SC dosing | PK Population | Posted | Mean | Standard Deviation | IU/dL | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
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| Secondary | PK Analysis - Half-Life and Residence Time | Summary of PK Parameters - Half-Life-1(alpha), Half-Life-1(beta), and Mean Residence Time | PK Population | Posted | Mean | Standard Deviation | days | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
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| Secondary | PK Analysis - Volume of Distribution at Steady-State Observed | Summary of PK Parameters - Volume of Distribution at Steady-State Observed | PK Population | Posted | Mean | Standard Deviation | dL/kg | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28. PK sampling was conducted on Day 1 (IV pre-dose -5 min, SC 30 min post IV dose, hour 7 +/- 1 hour) and Day 2 (hour 24 +/- 1 hour). |
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| Secondary | Occurrence of Clinical Thrombotic Event | Rate of occurrence of clinical thrombotic event not attributable to another cause | Safety Population | Posted | Count of Participants | Participants | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28 |
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| Secondary | Occurrence of an Antibody Response | Rate of occurrence of an antibody response to CB2679d and cross-reactive with wild-type recombinant coagulation FIX | Safety Population | Posted | Count of Participants | Participants | From date of first dose of CB2679d until date of first occurrence of clinical event, assessed up to treatment Day 28 |
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| Secondary | Thrombogenicity Assessment - Fibrinogen | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Pharmacodynamic Population | Posted | Mean | Standard Deviation | mg/dL | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
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| Secondary | Thrombogenicity Assessment - D-Dimer | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Pharmacodynamic Population | Posted | Mean | Standard Deviation | ug/L | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
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| Secondary | Thrombogenicity Assessment - Prothrombin Fragments 1 + 2 | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Pharmacodynamic Population | Posted | Mean | Standard Deviation | pmol/L | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
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| Secondary | Thrombogenicity Assessment - Thrombin/Antithrombin | Evaluation of the levels of thrombogenicity markers of a subcutaneous regimen of CB2679d | Pharmacodynamic Population | Posted | Mean | Standard Deviation | ug/L | Screening, Day 1 (IV Pre-dose, SC Dose), Day 2, 3, 7, 14, 21, 28, 29, 30, 31, 32, 33, and End of Study. End of Study is the average of each subject's last recorded assessment (between Days 29 to 33). |
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| 0 |
| 6 |
| 0 |
| 6 |
| 2 |
| 6 |
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| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D040181 | Genetic Diseases, X-Linked |
| Day 1, IV Predose |
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| Day 1, SC Dose |
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| Day 2 |
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| Day 3 |
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| Day 7 |
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| Day 14 |
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| Day 21 |
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| Day 28 |
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| Day 29 |
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| Day 30 |
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| Day 31 |
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| Day 32 |
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| Day 33 |
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| End of Study |
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| SC Maximum change from baseline during SC dosing |
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| Title | Measurements |
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| Fibrinogen - Day 1, IV Pre-dose |
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| Fibrinogen - Day 1, SC Dose |
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| Fibrinogen - Day 2 |
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| Fibrinogen - Day 3 |
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| Fibrinogen - Day 7 |
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| Fibrinogen - Day 14 |
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| Fibrinogen - Day 21 |
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| Fibrinogen - Day 28 |
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| Fibrinogen - Day 29 |
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| Fibrinogen - Day 30 |
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| Fibrinogen - Day 31 |
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| Fibrinogen - Day 32 |
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| Fibrinogen - Day 33 |
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| Fibrinogen - End of Study |
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| Fibrinogen - Maximum change from baseline during dosing |
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| D-Dimer - Day 1, IV Pre-dose |
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| D-Dimer - Day 1, SC Dose |
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| D-Dimer - Day 2 |
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| D-Dimer - Day 3 |
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| D-Dimer - Day 7 |
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| D-Dimer - Day 14 |
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| D-Dimer - Day 21 |
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| D-Dimer - Day 28 |
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| D-Dimer - Day 29 |
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| D-Dimer - Day 30 |
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| D-Dimer - Day 31 |
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| D-Dimer - Day 32 |
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| D-Dimer - Day 33 |
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| D-Dimer - End of Study |
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| D-Dimer - Maximum change from baseline during dosing |
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| Prothrombin Fragments 1 + 2 - Day 1, IV Pre-dose |
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| Prothrombin Fragments 1 + 2 - Day 1, SC Dose |
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| Prothrombin Fragments 1 + 2 - Day 2 |
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| Prothrombin Fragments 1 + 2 - Day 3 |
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| Prothrombin Fragments 1 + 2 - Day 7 |
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| Prothrombin Fragments 1 + 2 - Day 14 |
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| Prothrombin Fragments 1 + 2 - Day 21 |
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| Prothrombin Fragments 1 + 2 - Day 28 |
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| Prothrombin Fragments 1 + 2 - Day 29 |
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| Prothrombin Fragments 1 + 2 - Day 30 |
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| Prothrombin Fragments 1 + 2 - Day 31 |
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| Prothrombin Fragments 1 + 2 - Day 32 |
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| Prothrombin Fragments 1 + 2 - Day 33 |
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| Prothrombin Fragments 1 + 2 - End of Study |
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| Prothrombin Fragments 1 + 2 - Maximum change from baseline during dosing |
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| Thrombin/Antithrombin - Day 1, IV Pre-dose |
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| Thrombin/Antithrombin - Day 1, SC Dose |
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| Thrombin/Antithrombin - Day 2 |
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| Thrombin/Antithrombin - Day 3 |
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| Thrombin/Antithrombin - Day 7 |
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| Thrombin/Antithrombin - Day 14 |
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| Thrombin/Antithrombin - Day 21 |
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| Thrombin/Antithrombin - Day 28 |
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| Thrombin/Antithrombin - Day 29 |
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| Thrombin/Antithrombin - Day 30 |
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| Thrombin/Antithrombin - Day 31 |
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| Thrombin/Antithrombin - Day 32 |
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| Thrombin/Antithrombin - Day 33 |
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| Thrombin/Antithrombin - End of Study |
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| Thrombin/Antithrombin - Maximum change from baseline during dosing |
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