Hemophilia A, Hemophilia A With Inhibitor, Hemophilia A Without Inhibitor, Hemophilia B, Hemophilia B With Inhibitor, Hemophilia B Without Inhibitor
Conditions
Brief summary
This multi-center, open label Phase 1 study will evaluate the pharmacokinetics, pharmacodynamics, and safety of a single IV dose of MarzAA followed by ascending single SC doses of MarzAA in adult subjects with moderate or severe Hemophilia A or B, with or without an inhibitor.
Detailed description
This multi-center, open label Phase 1 study will evaluate the pharmacokinetics, pharmacodynamics, and safety of a single IV dose of MarzAA followed by ascending single SC doses of MarzAA in adult subjects with moderate or severe Hemophilia A or B, with or without an inhibitor. The study will enroll at least 8 adult male subjects with moderate or severe Hemophilia A or B with or without an inhibitor, in each dosing stage. Each subject will receive escalating doses of MarzAA for each stage of the study (except for Stage 5, where subjects receive the same dose as in Stage 4 split between two anatomical sites).
Interventions
BIOLOGICALMarzAA (marzeptacog alfa [activated])
Single intravenous dose and ascending doses of subcutaneous injection of MarzAA (Coagulation Faction VIIa Variant)
Sponsors
Catalyst Biosciences
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Moderate or severe congenital Hemophilia A or B, with or without an inhibitor * Male, age 18 or older * Affirmation of informed consent with signature confirmation before any trial related activities
Exclusion criteria
* Inability to discontinue and washout prophylaxis treatment 72 hours prior to dosing. * Previous participation in a trial involving SC Administration of rFVIIa or any trial using a modified amino-acid sequence FVIIa * Known positive antibody to FVII or FVIIa detected by central laboratory at screening * Have a coagulation disorder other than hemophilia A or B, with or without an inhibitor * Significant contraindication to participate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Comparative pharmacokinetics (PK) by dose level/stage based on examination of AUC frequencies of these for each of the dose groups |
| Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Comparative pharmacokinetics by dose level/stage based on examination of AUC frequency of these for each of the dose groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Change in T1/2eqα at each stage for each dose group |
| Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Change in T1/2λ-z at each stage for each dose group |
| Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Change in CL at each stage for each dose group |
| Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Change in Vd1 at each stage for each dose group |
| Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Change in BAabs at each stage for each dose group |
| Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Change in Mean Residence Time at each stage for each dose group |
| Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC From T1 to T2 Norm by Dose | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | PK analysis by route of administration, dose level/stage of the study based on examination of AUC for each of the dose groups. Split dose (2\*30 µg/kg) vs. (60 µg/kg) |
| Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | PK analysis by route of administration, dose level/stage of the study based on examination of AUC for each of the dose groups. Split dose (2\*30 µg/kg) vs. (60 µg/kg) |
| Change in Coagulation Parameters - Prothrombin Time (PT) | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-7 (SC). | Maximum change in PT from pre-dose |
| Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Change in Cmax at each stage for each dose group |
| Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | Maximum change in TGT parameter from pre-dose |
| Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | Maximum change in TGT parameters from pre-dose |
| Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | Maximum change in TGT parameter from pre-dose |
| Change in Thrombogenicity Parameter - Fibrinogen | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | Maximum change in thrombogenicity parameter from pre-dose |
| Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | Maximum change in thrombogenicity parameter from pre-dose |
| Change in Thrombogenicity Parameter - Thrombin/Antithrombin | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | Maximum change in thrombogenicity parameter from pre-dose |
| Change in Thrombogenicity Parameter - D-Dimer | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | Maximum change in thrombogenicity parameter from pre-dose |
| Occurrence of an Antibody Response to MarzAA | From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to End of Study. Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing. | Occurrence of an antibody response to MarzAA and whether it is inhibitory and cross-reactive to wild-type recombinant coagulation FVII (wt-rFVII) or wt-FVIIa |
| Occurrence of Clinical Thrombotic Event | From the date of first dose of MarzAA until date of first occurrence of clinical event, assessed up to End of Study. Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing. | Occurrence of clinical thrombotic event not attributable to another cause |
| Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | Maximum change in aPTT from pre-dose |
| Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | Change in Tmax at each stage for each dose group |
Countries
Bulgaria, Russia
Participant flow
Pre-assignment details
Fourteen subjects were screened in the study and three subjects were screen failures. Two subjects failed due to having a known positive antibody at screening, and one subject failed screening due to other.
Participants by arm
| Arm | Count |
|---|---|
| Study Population MarzAA (Marzeptacog Alfa \[activated\], Coagulation Factor VIIa variant) 18 µg/kg intravenously (Stage 1) followed by MarzAA 30 µg/kg subcutaneously (SC) (Stage 2), MarzAA 45 µg/kg SC (Stage 3), MarzAA 60 µg/kg SC (Stage 4), MarzAA 2x30 µg/kg SC (Stage 5), MarzAA 90 µg/kg SC (Stage 6), MarzAA 120 µg/kg SC (Stage 7), MarzAA 2×60 µg/kg SC (Stage 8), MarzAA 3x60 µg/kg SC (Stage 9) | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Region of Enrollment Bulgaria | 8 participants |
| Region of Enrollment Russia | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 11 | 3 / 8 | 0 / 8 | 1 / 8 | 1 / 8 | 0 / 8 | 2 / 8 | 3 / 8 | 2 / 8 |
| serious Total, serious adverse events | 0 / 11 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last
Comparative pharmacokinetics (PK) by dose level/stage based on examination of AUC frequencies of these for each of the dose groups
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-∞ | 1390.0 h*ng/mL | Standard Deviation 433.99 |
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-last | 1382.6 h*ng/mL | Standard Deviation 431.45 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-∞ | 516.4 h*ng/mL | Standard Deviation 170.01 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-last | 429.5 h*ng/mL | Standard Deviation 178.3 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-∞ | 849.4 h*ng/mL | Standard Deviation 275 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-last | 692.9 h*ng/mL | Standard Deviation 232.53 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-∞ | 1060.0 h*ng/mL | Standard Deviation 205.86 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-last | 922.1 h*ng/mL | Standard Deviation 192.38 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-∞ | 1025.6 h*ng/mL | Standard Deviation 328.31 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-last | 934.1 h*ng/mL | Standard Deviation 305.32 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-last | 1322.6 h*ng/mL | Standard Deviation 440.03 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-∞ | 1487.9 h*ng/mL | Standard Deviation 429.39 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-last | 1868.1 h*ng/mL | Standard Deviation 651.04 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-∞ | 2087.6 h*ng/mL | Standard Deviation 648.85 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-∞ | 2108.0 h*ng/mL | Standard Deviation 409 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-last | 1939.1 h*ng/mL | Standard Deviation 357.25 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-∞ | 3235.5 h*ng/mL | Standard Deviation 735.43 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | AUC0-last | 3038.1 h*ng/mL | Standard Deviation 760.56 |
Primary
Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose
Comparative pharmacokinetics by dose level/stage based on examination of AUC frequency of these for each of the dose groups
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | 76.81 h*kg/mL | Standard Deviation 23.97 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | 14.32 h*kg/mL | Standard Deviation 5.94 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | 15.40 h*kg/mL | Standard Deviation 5.17 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | 15.37 h*kg/mL | Standard Deviation 3.206 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | 15.57 h*kg/mL | Standard Deviation 5.09 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | 14.70 h*kg/mL | Standard Deviation 4.89 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | 15.57 h*kg/mL | Standard Deviation 5.43 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | 16.16 h*kg/mL | Standard Deviation 2.98 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | 16.88 h*kg/mL | Standard Deviation 4.23 |
Secondary
Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT)
Maximum change in aPTT from pre-dose
Time frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | -11.69 seconds | Standard Deviation 3.71 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | 1.91 seconds | Standard Deviation 3.21 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | -2.33 seconds | Standard Deviation 4.28 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | -2.18 seconds | Standard Deviation 2.63 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | -2.51 seconds | Standard Deviation 2.09 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | -2.85 seconds | Standard Deviation 1.82 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | -2.10 seconds | Standard Deviation 3.02 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | -2.92 seconds | Standard Deviation 3.01 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | -5.13 seconds | Standard Deviation 2.59 |
Secondary
Change in Coagulation Parameters - Prothrombin Time (PT)
Maximum change in PT from pre-dose
Time frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-7 (SC).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Change in Coagulation Parameters - Prothrombin Time (PT) | -1.36 seconds | Standard Deviation 0.57 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Coagulation Parameters - Prothrombin Time (PT) | -1.41 seconds | Standard Deviation 0.86 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Coagulation Parameters - Prothrombin Time (PT) | -1.16 seconds | Standard Deviation 0.68 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Coagulation Parameters - Prothrombin Time (PT) | -1.09 seconds | Standard Deviation 0.58 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Coagulation Parameters - Prothrombin Time (PT) | -1.29 seconds | Standard Deviation 0.86 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Coagulation Parameters - Prothrombin Time (PT) | -1.07 seconds | Standard Deviation 0.79 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Coagulation Parameters - Prothrombin Time (PT) | -1.37 seconds | Standard Deviation 0.54 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Coagulation Parameters - Prothrombin Time (PT) | -1.36 seconds | Standard Deviation 0.6 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Coagulation Parameters - Prothrombin Time (PT) | -1.35 seconds | Standard Deviation 0.62 |
Secondary
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential
Maximum change in TGT parameter from pre-dose
Time frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | 215.9 nM•minutes | Standard Deviation 337.55 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | 158.6 nM•minutes | Standard Deviation 247.55 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | 94.3 nM•minutes | Standard Deviation 148.51 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | 149.5 nM•minutes | Standard Deviation 256.34 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | 211.0 nM•minutes | Standard Deviation 190.22 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | 133.0 nM•minutes | Standard Deviation 193.85 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | 216.9 nM•minutes | Standard Deviation 184.54 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | 164.6 nM•minutes | Standard Deviation 58.49 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | -187.3 nM•minutes | Standard Deviation 474.61 |
Secondary
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak
Maximum change in TGT parameters from pre-dose
Time frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Lag | -1.30 minutes | Standard Deviation 1.231 |
| Stage 1 MarzAA 18 µg/kg IV | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Time to Peak | -3.88 minutes | Standard Deviation 3.302 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Lag | -1.21 minutes | Standard Deviation 0.613 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Time to Peak | -2.22 minutes | Standard Deviation 2.309 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Lag | -1.11 minutes | Standard Deviation 0.391 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Time to Peak | -2.76 minutes | Standard Deviation 1.226 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Lag | -1.42 minutes | Standard Deviation 0.645 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Time to Peak | -3.53 minutes | Standard Deviation 2.313 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Lag | -1.38 minutes | Standard Deviation 0.311 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Time to Peak | -3.68 minutes | Standard Deviation 1.29 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Time to Peak | -3.73 minutes | Standard Deviation 1.926 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Lag | -1.07 minutes | Standard Deviation 0.655 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Time to Peak | -3.73 minutes | Standard Deviation 2.024 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Lag | -1.33 minutes | Standard Deviation 0.396 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Lag | -1.54 minutes | Standard Deviation 0.507 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Time to Peak | -3.70 minutes | Standard Deviation 1.681 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Lag | -1.13 minutes | Standard Deviation 0.688 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | TGT-Time to Peak | -3.25 minutes | Standard Deviation 1.756 |
Secondary
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak
Maximum change in TGT parameter from pre-dose
Time frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | 64.0 nM | Standard Deviation 65.32 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | 14.9 nM | Standard Deviation 31.69 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | 28.3 nM | Standard Deviation 21.04 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | 42.3 nM | Standard Deviation 32.13 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | 45.4 nM | Standard Deviation 30.84 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | 33.0 nM | Standard Deviation 25.16 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | 44.3 nM | Standard Deviation 46.1 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | 45.6 nM | Standard Deviation 19.18 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | 41.3 nM | Standard Deviation 30.47 |
Secondary
Change in Thrombogenicity Parameter - D-Dimer
Maximum change in thrombogenicity parameter from pre-dose
Time frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Change in Thrombogenicity Parameter - D-Dimer | 0.141 mg/L Fibrinogen Equivalent Unit | Standard Deviation 0.214 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Thrombogenicity Parameter - D-Dimer | -0.054 mg/L Fibrinogen Equivalent Unit | Standard Deviation 0.104 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Thrombogenicity Parameter - D-Dimer | 0.110 mg/L Fibrinogen Equivalent Unit | Standard Deviation 0.08 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Thrombogenicity Parameter - D-Dimer | 0.039 mg/L Fibrinogen Equivalent Unit | Standard Deviation 0.073 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Thrombogenicity Parameter - D-Dimer | 0.285 mg/L Fibrinogen Equivalent Unit | Standard Deviation 0.605 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Thrombogenicity Parameter - D-Dimer | 0.200 mg/L Fibrinogen Equivalent Unit | Standard Deviation 0.175 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Thrombogenicity Parameter - D-Dimer | 0.211 mg/L Fibrinogen Equivalent Unit | Standard Deviation 0.285 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Thrombogenicity Parameter - D-Dimer | 0.111 mg/L Fibrinogen Equivalent Unit | Standard Deviation 0.125 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Thrombogenicity Parameter - D-Dimer | 0.256 mg/L Fibrinogen Equivalent Unit | Standard Deviation 0.173 |
Secondary
Change in Thrombogenicity Parameter - Fibrinogen
Maximum change in thrombogenicity parameter from pre-dose
Time frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Change in Thrombogenicity Parameter - Fibrinogen | -13.2 mg/dL | Standard Deviation 23.83 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Thrombogenicity Parameter - Fibrinogen | 13.3 mg/dL | Standard Deviation 29.65 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Thrombogenicity Parameter - Fibrinogen | -23.6 mg/dL | Standard Deviation 34.04 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Thrombogenicity Parameter - Fibrinogen | 16.0 mg/dL | Standard Deviation 37.67 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Thrombogenicity Parameter - Fibrinogen | 7.6 mg/dL | Standard Deviation 51.69 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Thrombogenicity Parameter - Fibrinogen | -31.0 mg/dL | Standard Deviation 42.02 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Thrombogenicity Parameter - Fibrinogen | 21.6 mg/dL | Standard Deviation 56.61 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Thrombogenicity Parameter - Fibrinogen | -12.5 mg/dL | Standard Deviation 32.74 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Thrombogenicity Parameter - Fibrinogen | -8.0 mg/dL | Standard Deviation 33.72 |
Secondary
Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2
Maximum change in thrombogenicity parameter from pre-dose
Time frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | 1903.5 pmol/L | Standard Deviation 3809.47 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | 206.3 pmol/L | Standard Deviation 545.97 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | 56.0 pmol/L | Standard Deviation 158.02 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | 76.5 pmol/L | Standard Deviation 118.78 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | 383.9 pmol/L | Standard Deviation 324.41 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | 974.5 pmol/L | Standard Deviation 2407.09 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | 1744.9 pmol/L | Standard Deviation 4367.48 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | 236.5 pmol/L | Standard Deviation 459.58 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | 284.9 pmol/L | Standard Deviation 672.8 |
Secondary
Change in Thrombogenicity Parameter - Thrombin/Antithrombin
Maximum change in thrombogenicity parameter from pre-dose
Time frame: From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Change in Thrombogenicity Parameter - Thrombin/Antithrombin | 105.09 µg/L | Standard Deviation 254.951 |
| Stage 2 MarzAA 30 µg/kg SC | Change in Thrombogenicity Parameter - Thrombin/Antithrombin | 62.34 µg/L | Standard Deviation 156.899 |
| Stage 3 MarzAA 45 µg/kg SC | Change in Thrombogenicity Parameter - Thrombin/Antithrombin | 10.41 µg/L | Standard Deviation 19.586 |
| Stage 4 MarzAA 60 µg/kg SC | Change in Thrombogenicity Parameter - Thrombin/Antithrombin | 63.57 µg/L | Standard Deviation 181.409 |
| Stage 5 MarzAA 2×30 µg/kg SC | Change in Thrombogenicity Parameter - Thrombin/Antithrombin | 138.19 µg/L | Standard Deviation 202.946 |
| Stage 6 MarzAA 90 µg/kg SC | Change in Thrombogenicity Parameter - Thrombin/Antithrombin | 56.79 µg/L | Standard Deviation 146.603 |
| Stage 7 MarzAA 120 µg/kg SC | Change in Thrombogenicity Parameter - Thrombin/Antithrombin | 10.46 µg/L | Standard Deviation 15.648 |
| Stage 8 2×60 µg/kg SC Q3H | Change in Thrombogenicity Parameter - Thrombin/Antithrombin | 18.90 µg/L | Standard Deviation 38.191 |
| Stage 9 3×60 µg/kg SC Q3H | Change in Thrombogenicity Parameter - Thrombin/Antithrombin | 3.75 µg/L | Standard Deviation 3.231 |
Secondary
Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs
Change in BAabs at each stage for each dose group
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | 100 Percentage | Standard Deviation 100 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | 19.47 Percentage | Standard Deviation 8.07 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | 21.52 Percentage | Standard Deviation 10.63 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | 21.32 Percentage | Standard Deviation 7.42 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | 20.87 Percentage | Standard Deviation 6.32 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | 19.84 Percentage | Standard Deviation 7.2 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | 21.24 Percentage | Standard Deviation 9.32 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | 23.00 Percentage | Standard Deviation 8.98 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | 23.32 Percentage | Standard Deviation 6.69 |
Secondary
Comparative MarzAA Activity of Intravenous and Subcutaneous - CL
Change in CL at each stage for each dose group
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | 14.22 mL/h | Standard Deviation 4.66 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | 63.33 mL/h | Standard Deviation 19.64 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | 57.85 mL/h | Standard Deviation 18.21 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | 58.88 mL/h | Standard Deviation 13.68 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | 63.92 mL/h | Standard Deviation 20.36 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | 65.13 mL/h | Standard Deviation 18.67 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | 64.39 mL/h | Standard Deviation 26.93 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | 59.05 mL/h | Standard Deviation 12.68 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | 58.22 mL/h | Standard Deviation 13.28 |
Secondary
Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax
Change in Cmax at each stage for each dose group
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | 419.49 ng/mL | Standard Deviation 185.18 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | 18.96 ng/mL | Standard Deviation 10.29 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | 32.91 ng/mL | Standard Deviation 18.49 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | 41.88 ng/mL | Standard Deviation 15.24 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | 40.75 ng/mL | Standard Deviation 15.98 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | 54.29 ng/mL | Standard Deviation 24.68 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | 76.70 ng/mL | Standard Deviation 34.51 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | 68.04 ng/mL | Standard Deviation 26.58 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | 98.33 ng/mL | Standard Deviation 32.64 |
Secondary
Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time
Change in Mean Residence Time at each stage for each dose group
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | 3.77 hours | Standard Deviation 0.42 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | 28.25 hours | Standard Deviation 9.18 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | 28.10 hours | Standard Deviation 9.94 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | 23.79 hours | Standard Deviation 5.4 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | 20.96 hours | Standard Deviation 5.58 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | 23.42 hours | Standard Deviation 7.47 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | 22.80 hours | Standard Deviation 5.9211 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | 29.04 hours | Standard Deviation 7.88 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | 29.32 hours | Standard Deviation 8.6 |
Secondary
Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα
Change in T1/2eqα at each stage for each dose group
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | 1.73 hours | Standard Deviation 0.55 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | NA hours | — |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | NA hours | — |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | NA hours | — |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | NA hours | — |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | NA hours | — |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | NA hours | — |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | NA hours | — |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | NA hours | — |
Secondary
Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z
Change in T1/2λ-z at each stage for each dose group
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | 3.3 hours | Standard Deviation 0.38 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | 18.55 hours | Standard Deviation 5.88 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | 19.26 hours | Standard Deviation 6.69 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | 15.70 hours | Standard Deviation 3.45 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | 13.05 hours | Standard Deviation 5.07 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | 15.50 hours | Standard Deviation 5.65 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | 15.03 hours | Standard Deviation 4.43 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | 18.82 hours | Standard Deviation 5.82 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | 18.07 hours | Standard Deviation 6.78 |
Secondary
Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax
Change in Tmax at each stage for each dose group
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | 0.17 hour | Standard Deviation 0.29 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | 7.50 hour | Standard Deviation 1.6 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | 7.38 hour | Standard Deviation 2.56 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | 8.25 hour | Standard Deviation 1.39 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | 6.75 hour | Standard Deviation 1.398 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | 7.12 hour | Standard Deviation 1.55 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | 8.25 hour | Standard Deviation 1.39 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | 8.37 hour | Standard Deviation 2.67 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | 12.25 hour | Standard Deviation 5.04 |
Secondary
Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1
Change in Vd1 at each stage for each dose group
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | 53.41 mL | Standard Deviation 18.02 |
| Stage 2 MarzAA 30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | 1868.28 mL | Standard Deviation 962.02 |
| Stage 3 MarzAA 45 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | 1651.05 mL | Standard Deviation 799.32 |
| Stage 4 MarzAA 60 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | 1400.41 mL | Standard Deviation 478.92 |
| Stage 5 MarzAA 2×30 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | 1344.19 mL | Standard Deviation 557.26 |
| Stage 6 MarzAA 90 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | 1577.63 mL | Standard Deviation 791.28 |
| Stage 7 MarzAA 120 µg/kg SC | Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | 1509.24 mL | Standard Deviation 796.5 |
| Stage 8 2×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | 1699.49 mL | Standard Deviation 474.39 |
| Stage 9 3×60 µg/kg SC Q3H | Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | 1717.33 mL | Standard Deviation 629.45 |
Secondary
Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC From T1 to T2 Norm by Dose
PK analysis by route of administration, dose level/stage of the study based on examination of AUC for each of the dose groups. Split dose (2\*30 µg/kg) vs. (60 µg/kg)
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC From T1 to T2 Norm by Dose | 15.3687 h*kg/mL | Standard Deviation 3.2063 |
| Stage 2 MarzAA 30 µg/kg SC | Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC From T1 to T2 Norm by Dose | 15.5688 h*kg/mL | Standard Deviation 5.08859 |
Secondary
Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc
PK analysis by route of administration, dose level/stage of the study based on examination of AUC for each of the dose groups. Split dose (2\*30 µg/kg) vs. (60 µg/kg)
Time frame: Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc | AUC Infinity Obs | 1060.0 h*ng/mL | Standard Deviation 205.86 |
| Stage 1 MarzAA 18 µg/kg IV | Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc | AUC to Last Nonzero Conc | 922.1 h*ng/mL | Standard Deviation 192.38 |
| Stage 2 MarzAA 30 µg/kg SC | Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc | AUC Infinity Obs | 1025.6 h*ng/mL | Standard Deviation 328.31 |
| Stage 2 MarzAA 30 µg/kg SC | Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc | AUC to Last Nonzero Conc | 934.1 h*ng/mL | Standard Deviation 305.32 |
Secondary
Occurrence of an Antibody Response to MarzAA
Occurrence of an antibody response to MarzAA and whether it is inhibitory and cross-reactive to wild-type recombinant coagulation FVII (wt-rFVII) or wt-FVIIa
Time frame: From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to End of Study. Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Occurrence of an Antibody Response to MarzAA | 0 participants with an occurrence |
| Stage 2 MarzAA 30 µg/kg SC | Occurrence of an Antibody Response to MarzAA | 0 participants with an occurrence |
| Stage 3 MarzAA 45 µg/kg SC | Occurrence of an Antibody Response to MarzAA | 0 participants with an occurrence |
| Stage 4 MarzAA 60 µg/kg SC | Occurrence of an Antibody Response to MarzAA | 0 participants with an occurrence |
| Stage 5 MarzAA 2×30 µg/kg SC | Occurrence of an Antibody Response to MarzAA | 0 participants with an occurrence |
| Stage 6 MarzAA 90 µg/kg SC | Occurrence of an Antibody Response to MarzAA | 0 participants with an occurrence |
| Stage 7 MarzAA 120 µg/kg SC | Occurrence of an Antibody Response to MarzAA | 0 participants with an occurrence |
| Stage 8 2×60 µg/kg SC Q3H | Occurrence of an Antibody Response to MarzAA | 0 participants with an occurrence |
| Stage 9 3×60 µg/kg SC Q3H | Occurrence of an Antibody Response to MarzAA | 0 participants with an occurrence |
Secondary
Occurrence of Clinical Thrombotic Event
Occurrence of clinical thrombotic event not attributable to another cause
Time frame: From the date of first dose of MarzAA until date of first occurrence of clinical event, assessed up to End of Study. Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stage 1 MarzAA 18 µg/kg IV | Occurrence of Clinical Thrombotic Event | 0 participants with an occurrence |
| Stage 2 MarzAA 30 µg/kg SC | Occurrence of Clinical Thrombotic Event | 0 participants with an occurrence |
| Stage 3 MarzAA 45 µg/kg SC | Occurrence of Clinical Thrombotic Event | 0 participants with an occurrence |
| Stage 4 MarzAA 60 µg/kg SC | Occurrence of Clinical Thrombotic Event | 0 participants with an occurrence |
| Stage 5 MarzAA 2×30 µg/kg SC | Occurrence of Clinical Thrombotic Event | 0 participants with an occurrence |
| Stage 6 MarzAA 90 µg/kg SC | Occurrence of Clinical Thrombotic Event | 0 participants with an occurrence |
| Stage 7 MarzAA 120 µg/kg SC | Occurrence of Clinical Thrombotic Event | 0 participants with an occurrence |
| Stage 8 2×60 µg/kg SC Q3H | Occurrence of Clinical Thrombotic Event | 0 participants with an occurrence |
| Stage 9 3×60 µg/kg SC Q3H | Occurrence of Clinical Thrombotic Event | 0 participants with an occurrence |