Hereditary Angioedema
Conditions
Brief summary
This is a multicenter, randomized, placebo-controlled, parallel-arm, phase 2 study to investigate the clinical efficacy, pharmacokinetics, and safety of CSL312 as prophylaxis to prevent attacks in subjects with HAE.
Interventions
BIOLOGICALFactor XIIa antagonist monoclonal antibody
Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use
DRUGPlacebo
Buffer without active ingredient
Sponsors
CSL Behring
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind
Intervention model description
Subjects are assigned to 1 of 2 or more groups in parallel for the duration of the study
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female * Aged ≥ 18 to ≤ 65 years * A diagnosis of C1-INH HAE or FXII/PLG HAE; * For subjects with C1-INH HAE: ≥ 4 HAE attacks over a consecutive 2-month period during the 3 months before Screening, as documented in the subject's medical record.
Exclusion criteria
* History of clinically significant arterial or venous thrombosis, or current clinically significant prothrombotic risk * History of an uncontrolled, abnormal bleeding event due to a coagulopathy, or a current clinically significant coagulopathy or clinically significant risks for bleeding events * Known incurable malignancies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Mean Time Normalized Number of HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | The time-normalized number of HAE attacks per month during Treatment Period 1 for a subject was calculated as the (number of HAE attacks / length of subject's evaluation period in days) \* 30.4375 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Responder Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | Response is defined as a ≥ 50% relative reduction in the time-normalized number of HAE attacks (per month) during Treatment Period 1 compared to each subject's time-normalized number of HAE attacks (per month) during the Run-in Period. |
| The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| The Number of Responder Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | Response is defined as a ≥ 50% relative reduction in the time-normalized number of HAE attacks (per month) during Treatment Period 1 compared to each subject's time-normalized number of HAE attacks (per month) during the Run-in Period |
| The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | The time-normalized number of HAE attacks per month during Treatment Period 1 for a subject was calculated as the (number of HAE attacks / length of subject's evaluation period in days) \* 30.4375 |
| The Number of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| Maximum Concentration (Cmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| Area Under the Concentration-time Curve in 1 Dosing Interval (AUC0-tau) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| Time of Maximum Concentration (Tmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| Terminal Elimination Half-life (T1/2) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| Clearance (CL/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| Volume of Distribution During the Elimination Phase (Vz/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
| The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | 13 weeks | Adverse events of special interest is defined as anaphylaxis, thromboembolic events, and bleeding events. |
| The Percentage of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 13 weeks | — |
Countries
Australia, Canada, Germany, Israel, United States
Participant flow
Pre-assignment details
Treatment Period 1 participants were assigned to 1 of 5 treatment arms. Treatment period 2 participants that completed Treatment Period 1 were assigned to either CSL312 (medium) or CSL312 (high) and could be up-titrated from CSL312 (medium) to CSL312 (med/high), if necessary. They were down-titrated from CSL312 (high) to CSL312 (medium). Only 2 subjects from the CSL312 (FXII/PLG HAE) arm were treated with CSL312 in Treatment Period 2.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects with C1-INH HAE (Hereditary angioedema with C1-esterase inhibitor deficiency) receiving buffer only
Placebo: Buffer without active ingredient | 8 |
| CSL312 (Low) Subjects with C1-INH HAE (Hereditary angioedema with C1-esterase inhibitor deficiency)receiving low dose CSL312
Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use | 9 |
| CSL312 (Med) Subjects with C1-INH HAE (Hereditary angioedema with C1-esterase inhibitor deficiency) receiving medium dose CSL312
Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use | 8 |
| CSL312 (High) Subjects with C1-INH HAE (Hereditary angioedema with C1-esterase inhibitor deficiency)receiving high dose CSL312
Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use | 7 |
| CSL312 (Med/High) Subjects with C1-INH HAE (Hereditary angioedema with C1-esterase inhibitor deficiency) receiving medium/high dose CSL312
Factor XIIa antagonist monoclonal antibody: Factor XIIa antagonist monoclonal antibody for intravenous and subcutaneous use | 6 |
| CSL312 (FXII/PLG HAE) Subjects with FXII/PLG HAE (Hereditary Angioedema with Normal C1-esterase Inhibitor and Factor XII or Plasminogen Gene Mutation) receiving high dose CSL312 | 6 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Period 2 | Pregnancy | 0 | 0 | 0 | 1 | 0 | 0 |
| Treatment Period 2 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | CSL312 (Low) | CSL312 (Med) | CSL312 (High) | CSL312 (Med/High) | CSL312 (FXII/PLG HAE) | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 9 Participants | 8 Participants | 6 Participants | 6 Participants | 6 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 9 Participants | 8 Participants | 7 Participants | 5 Participants | 6 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 9 Participants | 8 Participants | 5 Participants | 4 Participants | 6 Participants | 39 Participants |
| Region of Enrollment Canada | 1 participants | 3 participants | 2 participants | 1 participants | 0 participants | 0 participants | 7 participants |
| Region of Enrollment Germany | 3 participants | 2 participants | 4 participants | 3 participants | 2 participants | 3 participants | 17 participants |
| Region of Enrollment Israel | 0 participants | 2 participants | 2 participants | 1 participants | 2 participants | 2 participants | 9 participants |
| Region of Enrollment United States | 4 participants | 2 participants | 0 participants | 2 participants | 2 participants | 1 participants | 11 participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 2 Participants | 5 Participants | 3 Participants | 6 Participants | 27 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants | 2 Participants | 3 Participants | 0 Participants | 17 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 | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 7 | 0 / 6 | 0 / 36 | 0 / 3 | 0 / 18 | 0 / 6 | 0 / 2 |
| other Total, other adverse events | 7 / 8 | 7 / 9 | 7 / 8 | 7 / 7 | 4 / 6 | 25 / 36 | 2 / 3 | 17 / 18 | 1 / 6 | 2 / 2 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 | 0 / 8 | 0 / 7 | 0 / 6 | 1 / 36 | 0 / 3 | 1 / 18 | 1 / 6 | 0 / 2 |
Outcome results
Primary
The Mean Time Normalized Number of HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1
The time-normalized number of HAE attacks per month during Treatment Period 1 for a subject was calculated as the (number of HAE attacks / length of subject's evaluation period in days) \* 30.4375
Time frame: 13 weeks
Population: The Intent-to-Treat (ITT) population consisted of all subjects who provided informed consent, underwent any study screening procedure, and who were assigned to treatment in Treatment Period 1 or to treatment in Treatment Period 2, regardless of whether they received investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Mean Time Normalized Number of HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | 4.24 Number of HAE attacks per month | Standard Deviation 1.801 |
| CSL312 (Low) | The Mean Time Normalized Number of HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | 0.48 Number of HAE attacks per month | Standard Deviation 1.057 |
| CSL312 (Med) | The Mean Time Normalized Number of HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | 0.05 Number of HAE attacks per month | Standard Deviation 0.127 |
| CSL312 (High) | The Mean Time Normalized Number of HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | 0.35 Number of HAE attacks per month | Standard Deviation 0.407 |
| CSL312 (Med/High) | The Mean Time Normalized Number of HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | 0.14 Number of HAE attacks per month | Standard Deviation 0.222 |
Secondary
Area Under the Concentration-time Curve in 1 Dosing Interval (AUC0-tau) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: PK
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CSL312 (Low) | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC0-tau) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 4507 h*μg/mL | Standard Deviation 2424 |
| CSL312 (Med) | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC0-tau) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 7166 h*μg/mL | Standard Deviation 2410 |
| CSL312 (High) | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC0-tau) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 26514 h*μg/mL | Standard Deviation 8151 |
Secondary
Clearance (CL/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: PK
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CSL312 (Low) | Clearance (CL/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 0.0198 L/hour | Standard Deviation 0.0079 |
| CSL312 (Med) | Clearance (CL/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 0.0303 L/hour | Standard Deviation 0.0084 |
| CSL312 (High) | Clearance (CL/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 0.0246 L/hour | Standard Deviation 0.0079 |
Secondary
Maximum Concentration (Cmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: The pharmacokinetic (PK) population consisted of all subjects in the Safety population for whom at least 1 measurable concentration of CSL312 was reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CSL312 (Low) | Maximum Concentration (Cmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 10.6 ug/mL | Standard Deviation 6.09 |
| CSL312 (Med) | Maximum Concentration (Cmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 15.9 ug/mL | Standard Deviation 5.22 |
| CSL312 (High) | Maximum Concentration (Cmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 56.4 ug/mL | Standard Deviation 15.9 |
Secondary
Terminal Elimination Half-life (T1/2) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: PK
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CSL312 (Low) | Terminal Elimination Half-life (T1/2) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 411.7 hours | Standard Deviation 96.97 |
| CSL312 (Med) | Terminal Elimination Half-life (T1/2) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 394.0 hours | Standard Deviation 85.64 |
| CSL312 (High) | Terminal Elimination Half-life (T1/2) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 443.5 hours | Standard Deviation 44 |
Secondary
The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1
The time-normalized number of HAE attacks per month during Treatment Period 1 for a subject was calculated as the (number of HAE attacks / length of subject's evaluation period in days) \* 30.4375
Time frame: 13 weeks
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0.89 Number of HAE attacks per month | Standard Deviation 1.365 |
| Placebo | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 1.93 Number of HAE attacks per month | Standard Deviation 1.403 |
| Placebo | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 1.42 Number of HAE attacks per month | Standard Deviation 1.395 |
| CSL312 (Low) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0.0 Number of HAE attacks per month | Standard Deviation 0 |
| CSL312 (Low) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 0.12 Number of HAE attacks per month | Standard Deviation 0.177 |
| CSL312 (Low) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 0.36 Number of HAE attacks per month | Standard Deviation 1.087 |
| CSL312 (Med) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 0.05 Number of HAE attacks per month | Standard Deviation 0.127 |
| CSL312 (Med) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 0.0 Number of HAE attacks per month | Standard Deviation 0 |
| CSL312 (Med) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0.0 Number of HAE attacks per month | Standard Deviation 0 |
| CSL312 (High) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 0.10 Number of HAE attacks per month | Standard Deviation 0.168 |
| CSL312 (High) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 0.20 Number of HAE attacks per month | Standard Deviation 0.347 |
| CSL312 (High) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0.05 Number of HAE attacks per month | Standard Deviation 0.136 |
| CSL312 (Med/High) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0.0 Number of HAE attacks per month | Standard Deviation 0 |
| CSL312 (Med/High) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 0.14 Number of HAE attacks per month | Standard Deviation 0.222 |
| CSL312 (Med/High) | The Mean Time-normalized Number of Mild, Moderate or Severe HAE Attacks Per Month in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 0.0 Number of HAE attacks per month | Standard Deviation 0 |
Secondary
The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 0 Number of participants |
| CSL312 (Low) | The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 5 Number of participants |
| CSL312 (Med) | The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 7 Number of participants |
| CSL312 (High) | The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 3 Number of participants |
| CSL312 (Med/High) | The Number of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 4 Number of participants |
Secondary
The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 32 Number of HAE attacks |
| Placebo | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 20 Number of HAE attacks |
| Placebo | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 43 Number of HAE attacks |
| CSL312 (Low) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 9 Number of HAE attacks |
| CSL312 (Low) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 3 Number of HAE attacks |
| CSL312 (Low) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0 Number of HAE attacks |
| CSL312 (Med) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 1 Number of HAE attacks |
| CSL312 (Med) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 0 Number of HAE attacks |
| CSL312 (Med) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0 Number of HAE attacks |
| CSL312 (High) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 2 Number of HAE attacks |
| CSL312 (High) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 1 Number of HAE attacks |
| CSL312 (High) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 4 Number of HAE attacks |
| CSL312 (Med/High) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 0 Number of HAE attacks |
| CSL312 (Med/High) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 2 Number of HAE attacks |
| CSL312 (Med/High) | The Number of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0 Number of HAE attacks |
Secondary
The Number of Responder Subjects With C1-INH HAE During Treatment Period 1
Response is defined as a ≥ 50% relative reduction in the time-normalized number of HAE attacks (per month) during Treatment Period 1 compared to each subject's time-normalized number of HAE attacks (per month) during the Run-in Period
Time frame: 13 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Number of Responder Subjects With C1-INH HAE During Treatment Period 1 | 0 Number of participants |
| CSL312 (Low) | The Number of Responder Subjects With C1-INH HAE During Treatment Period 1 | 9 Number of participants |
| CSL312 (Med) | The Number of Responder Subjects With C1-INH HAE During Treatment Period 1 | 8 Number of participants |
| CSL312 (High) | The Number of Responder Subjects With C1-INH HAE During Treatment Period 1 | 6 Number of participants |
| CSL312 (Med/High) | The Number of Responder Subjects With C1-INH HAE During Treatment Period 1 | 6 Number of participants |
Secondary
The Number of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Number of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 8 Number of participants |
| CSL312 (Low) | The Number of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 3 Number of participants |
| CSL312 (Med) | The Number of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 1 Number of participants |
| CSL312 (High) | The Number of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 2 Number of participants |
| CSL312 (Med/High) | The Number of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 0 Number of participants |
Secondary
The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1
Adverse events of special interest is defined as anaphylaxis, thromboembolic events, and bleeding events.
Time frame: 13 weeks
Population: The Safety population (SP) consisted of all subjects who provided informed consent, were assigned to treatment in Treatment Period 1 or to treatment in Treatment Period 2 and received at least 1 dose or partial dose of investigational product and was based on the actual treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | ISRs | 2 Number of participants |
| Placebo | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AEs | 7 Number of participants |
| Placebo | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | Binding Antibodies to CSL312 | 1 Number of participants |
| Placebo | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | SAEs | 0 Number of participants |
| Placebo | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AESI | 1 Number of participants |
| CSL312 (Low) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | ISRs | 1 Number of participants |
| CSL312 (Low) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AESI | 0 Number of participants |
| CSL312 (Low) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | SAEs | 0 Number of participants |
| CSL312 (Low) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | Binding Antibodies to CSL312 | 0 Number of participants |
| CSL312 (Low) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AEs | 7 Number of participants |
| CSL312 (Med) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AESI | 0 Number of participants |
| CSL312 (Med) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AEs | 7 Number of participants |
| CSL312 (Med) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | SAEs | 0 Number of participants |
| CSL312 (Med) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | ISRs | 1 Number of participants |
| CSL312 (Med) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | Binding Antibodies to CSL312 | 0 Number of participants |
| CSL312 (High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | Binding Antibodies to CSL312 | 0 Number of participants |
| CSL312 (High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AEs | 7 Number of participants |
| CSL312 (High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | ISRs | 4 Number of participants |
| CSL312 (High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AESI | 0 Number of participants |
| CSL312 (High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | SAEs | 0 Number of participants |
| CSL312 (Med/High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AESI | 0 Number of participants |
| CSL312 (Med/High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | ISRs | 2 Number of participants |
| CSL312 (Med/High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | AEs | 4 Number of participants |
| CSL312 (Med/High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | Binding Antibodies to CSL312 | 0 Number of participants |
| CSL312 (Med/High) | The Number of Subjects With C1-INH HAE With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI), Injection Site Reactions (ISRs), Binding Antibodies to CSL312 During Treatment Period 1 | SAEs | 0 Number of participants |
Secondary
The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 0 percentage of participants |
| CSL312 (Low) | The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 55.6 percentage of participants |
| CSL312 (Med) | The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 87.5 percentage of participants |
| CSL312 (High) | The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 42.9 percentage of participants |
| CSL312 (Med/High) | The Percentage of HAE Attack-free Subjects With C1-INH HAE During Treatment Period 1 | 66.7 percentage of participants |
Secondary
The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 33.7 percentage of HAE attacks |
| Placebo | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 21.1 percentage of HAE attacks |
| Placebo | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 45.3 percentage of HAE attacks |
| CSL312 (Low) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 75.0 percentage of HAE attacks |
| CSL312 (Low) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 25.0 percentage of HAE attacks |
| CSL312 (Low) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0 percentage of HAE attacks |
| CSL312 (Med) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 100.0 percentage of HAE attacks |
| CSL312 (Med) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 0 percentage of HAE attacks |
| CSL312 (Med) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0 percentage of HAE attacks |
| CSL312 (High) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 28.6 percentage of HAE attacks |
| CSL312 (High) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 14.3 percentage of HAE attacks |
| CSL312 (High) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 57.1 percentage of HAE attacks |
| CSL312 (Med/High) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Moderate | 0 percentage of HAE attacks |
| CSL312 (Med/High) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Mild | 100.0 percentage of HAE attacks |
| CSL312 (Med/High) | The Percentage of Mild, Moderate or Severe HAE Attacks in Subjects With C1-INH HAE During Treatment Period 1 | Severe | 0 percentage of HAE attacks |
Secondary
The Percentage of Responder Subjects With C1-INH HAE During Treatment Period 1
Response is defined as a ≥ 50% relative reduction in the time-normalized number of HAE attacks (per month) during Treatment Period 1 compared to each subject's time-normalized number of HAE attacks (per month) during the Run-in Period.
Time frame: 13 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Responder Subjects With C1-INH HAE During Treatment Period 1 | 0 percentage of participants |
| CSL312 (Low) | The Percentage of Responder Subjects With C1-INH HAE During Treatment Period 1 | 100.0 percentage of participants |
| CSL312 (Med) | The Percentage of Responder Subjects With C1-INH HAE During Treatment Period 1 | 100.0 percentage of participants |
| CSL312 (High) | The Percentage of Responder Subjects With C1-INH HAE During Treatment Period 1 | 85.7 percentage of participants |
| CSL312 (Med/High) | The Percentage of Responder Subjects With C1-INH HAE During Treatment Period 1 | 100.0 percentage of participants |
Secondary
The Percentage of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 100.0 percentage of participants |
| CSL312 (Low) | The Percentage of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 33.3 percentage of participants |
| CSL312 (Med) | The Percentage of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 12.5 percentage of participants |
| CSL312 (High) | The Percentage of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 28.6 percentage of participants |
| CSL312 (Med/High) | The Percentage of Subjects With at Least One (1) HAE Attack Treated With On-demand HAE Medication, in Subjects With C1-INH HAE During Treatment Period 1 | 0 percentage of participants |
Secondary
Time of Maximum Concentration (Tmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: PK
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CSL312 (Low) | Time of Maximum Concentration (Tmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 143.38 hours |
| CSL312 (Med) | Time of Maximum Concentration (Tmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 165.51 hours |
| CSL312 (High) | Time of Maximum Concentration (Tmax) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 165.63 hours |
Secondary
Volume of Distribution During the Elimination Phase (Vz/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1
Time frame: 13 weeks
Population: PK
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CSL312 (Low) | Volume of Distribution During the Elimination Phase (Vz/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 10.6 Liters | Standard Deviation 5.1 |
| CSL312 (Med) | Volume of Distribution During the Elimination Phase (Vz/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 17.0 Liters | Standard Deviation 4.78 |
| CSL312 (High) | Volume of Distribution During the Elimination Phase (Vz/F) of CSL312 in Subjects With C1-INH HAE During Treatment Period 1 | 17.1 Liters | Standard Deviation 6.67 |