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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
6
Single intravenous injection of CB2679d/Dalcinonacog alfa
Daily subcutaneous injections of CB2679d/Dalcinonacog alfa for 28 days
Haemophilia Comprehensive Care Centre
Johannesburg, South Africa
Number of Subjects Who Achieved FIX Level ≥12%
Subjects who achieved a FIX activity level ≥12% during the treatment period in the PK Population
Time frame: Days 7, 14, 21, 28, 29
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.
Time frame: 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
Time frame: 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
Time frame: 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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PK Analysis - Maximum Concentration During SC Dosing
Summary of PK Parameters - Maximum Concentration during SC dosing
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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).