Hereditary Angioedema
Conditions
Brief summary
This phase 3b study will evaluate long-term safety and efficacy of CSL312 (also known as garadacimab) when administered subcutaneously (SC)
Interventions
BIOLOGICALCSL312
Fully human immunoglobulin G subclass 4/lambda recombinant inhibitor monoclonal antibody
Sponsors
CSL Behring
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females aged ≥ 12 years * Diagnosed with clinically confirmed C1-INH HAE * Experienced ≥ 3 HAE attacks during the 3 months before Screening * Participated in the Run-in Period for at least 1 month (CSL312-naïve subjects only) * Experienced at least an average of 1 HAE attack per month during the Run-in Period
Exclusion criteria
* Concomitant diagnosis of another form of angioedema, such as idiopathic or acquired angioedema or recurrent angioedema associated with urticaria * Use of C1-INH products, androgens, antifibrinolytics or other small molecule medications for routine prophylaxis against HAE attacks at least 2 weeks before the first day of the Run-in Period * Use of monoclonal antibodies such as lanadelumab (Takhzyro®) 3 months before the first day of the Run-in Period. * Female subjects use estrogen-containing oral contraceptives or hormone replacement therapy within 4 weeks prior to screening * Female or male subjects who are fertile and sexually active not using or not willing to use an acceptable method of contraception to avoid pregnancy during the study and for 30 days after receipt of the last dose of CSL312 * Pregnant, breastfeeding, or not willing to cease breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAE) | Approximately up to 54 months | — |
| Percentage of Participants With TEAE | Approximately up to 54 months | The percentage of participants was rounded to one place of decimal. |
| Number of TEAE | Approximately up to 54 months | — |
| TEAE Rates Per Injection | Approximately up to 54 months | The TEAE rate per injection was calculated as the number of TEAE/ total number of injections. The number of injections was defined as the total injections received by participants during the respective safety evaluation period. |
| TEAE Rates Per Participant Year | Approximately up to 54 months | The TEAE rate per participant year was calculated as the total number of TEAE/ participant years. Participant years was defined as the sum of the time (in years) that participant were exposed to study treatment during the respective safety evaluation period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Time-normalized Number (Per Month) of Hereditary Angioedema (HAE) Attacks During the Run-in Period and Treatment Period | Run-in Period: Up to Day 60 and Treatment Period: Approximately up to 52 months | Time-normalized number of HAE attacks per month during treatment was calculated per participant as: \[number of HAE attacks / length of participant treatment in days\]\*30.4375. |
| The Time-normalized Number (Per Year) of HAE Attacks During Treatment Period | Approximately up to 52 months | Time-normalized number of HAE attacks per year during treatment was calculated per participant as: \[number of HAE attacks / length of participant treatment in days\]\*365.25. |
| Percentage Reduction in the Attack Rate During the Treatment Period Compared to the Run-in Period | Run-in Period: Up to 60 days and Treatment Period: Approximately up to 52 months | The percentage reduction in the time-normalized number of HAE attacks was calculated within a participant as: 100\*(1- time normalized number of HAE attacks per month during Treatment Period/time-normalized number of HAE attacks per month during Run-in Period). |
| Number of Participants With Percentage Reduction (of >=50%, >=70%, >=90%, and 100%) in HAE Attacks | Run-in Period: Up to Day 60 and Treatment Period: Approximately up to 52 months | The number of participants who achieved a percentage reduction in HAE attacks of \>=50% (also considered as responders), \>=70%, \>=90%, and 100% (attack free) during the Treatment Period compared with the Run-in Period. The percentage reduction in the time-normalized number of HAE attacks per month was calculated as 100\*\[1 - (time-normalized number of HAE attacks per month under CSL312 treatment / time-normalized number of HAE attacks per month during Run-in Period)\]. |
| The Time-normalized Number (Per Month) of HAE Attacks Requiring On-demand Treatment | Approximately up to 52 months | Time-normalized number of HAE attacks per month requiring on demand treatment was calculated per participant as: \[number of HAE attacks requiring on demand treatment during treatment period / length of participant treatment in days\]\*30.4375. |
| The Time-normalized Number (Per Year) of HAE Attacks Requiring On-demand Treatment | Approximately up to 52 months | Time-normalized number of HAE attacks requiring on demand treatment per year was calculated per participant as: \[number of HAE attacks requiring on demand treatment during treatment period / length of participant treatment in days\]\*365.25. |
| The Time-normalized Number (Per Month) of Moderate and/or Severe HAE Attacks | Approximately up to 52 months | Time-normalized number of moderate or severe HAE attacks per month during treatment period was calculated per participant as: \[number of moderate or severe HAE attacks / length of participant treatment in days\]\*30.4375. |
| The Time-normalized Number (Per Year) of Moderate and/or Severe HAE Attacks | Approximately up to 52 months | Time-normalized number of moderate or severe HAE attacks per year during treatment period was calculated per participant as: \[number of moderate or severe HAE attacks /length of participant treatment in days\]\*365.25. |
| Number of Participants Rating Their Response to Therapy as Good or Excellent | At Months 12, 24, and 36 | Number of participants rating their response to therapy as good or excellent was evaluated as per Subject's Global Assessment of Response to Therapy (SGART) questionnaire. SGART is a patient-reported outcome that represents the participant's overall response to treatment using the following ratings: (0) none: worse or no response at all, not acceptable, (1) poor: very little response, not acceptable, (2) fair: some response, acceptable but could be better, (3) good: good response, acceptable, and (4) excellent: excellent response, as good as can be imagined. Cumulative responses as "Good or Excellent" are reported for this outcome measure. |
| Percentage of Participants Rating Their Response to Therapy as Good or Excellent | At Months 12, 24, and 36 | Percentage of participants rating their response to therapy as good or excellent was evaluated as per SGART questionnaire. SGART is a patient-reported outcome that represents the participant's overall response to treatment using the following ratings: (0) none: worse or no response at all, not acceptable, (1) poor: very little response, not acceptable, (2) fair: some response, acceptable but could be better, (3) good: good response, acceptable, and (4) excellent: excellent response, as good as can be imagined. Cumulative responses as "Good or Excellent" are reported for this outcome measure. The percentage of participants was rounded to one place of decimal. |
| Number of Participants Experiencing Serious Adverse Events (SAE), Experiencing Death, Related TEAE, TEAE Leading to Study Discontinuation | Approximately up to 54 months | — |
| Percentage of Participants Experiencing SAE, Experiencing Death, Related TEAE, TEAE Leading to Study Discontinuation | Approximately up to 54 months | The percentage of participants was rounded to one decimal place. |
| Number of Participants Experiencing TEAE by Severity | Approximately up to 54 months | Severity of AE was assessed by the investigator and categorized as mild, moderate and severe. A mild AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living. A moderate AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant. A severe AE that interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention. |
| Percentage of Participants Experiencing TEAE by Severity | Approximately up to 54 months | Severity of AE was assessed by the investigator and categorized as mild, moderate and severe. A mild AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living. A moderate AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant. A severe AE that interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention. The percentage of participants was rounded to one decimal place. |
| Number of Participants Experiencing Adverse Events of Special Interest (AESI) | Approximately up to 54 months | The AESI defined for this study were thromboembolic events, abnormal bleeding events, and severe hypersensitivity including anaphylaxis. The AESI reported have been identified by investigators. |
| Percentage of Participants Experiencing AESI | Approximately up to 54 months | The AESI defined for this study were thromboembolic events, abnormal bleeding events, and severe hypersensitivity including anaphylaxis. The AESI reported have been identified by investigators. |
| Number of Participants With Laboratory Findings Reported as TEAE | Approximately up to 54 months | — |
| Percentage of Participants With Laboratory Findings Reported as TEAE | Approximately up to 54 months | The percentage of participant was rounded to one place of decimal. |
| Number of Participants With Normal C1-esterase Inhibitor (nC1-INH) Experiencing TEAE | Approximately up to 54 months | — |
| Percentage of Participants With nC1-INH Experiencing TEAE | Approximately up to 54 months | — |
| Number of Participants With Anti-CSL312 Antibodies | At Day 1, Months 6, 12, 36 and 43 (end of treatment [EOT]) | — |
| Percentage of Participants With Anti-CSL312 Antibodies | At Day 1, Months 6, 12, 36 and 43 (EOT) | The percentage of participants was rounded to one decimal place. |
Countries
Australia, Canada, Czechia, Germany, Hong Kong, Hungary, Israel, Japan, Netherlands, New Zealand, Russia, Spain, Taiwan, United States
Contacts
STUDY_DIRECTORStudy Director
CSL Behring
Participant flow
Recruitment details
This study was conducted at 44 sites in 14 countries (Australia, Canada, Czechia, Germany, Hong Kong, Hungary, Israel, Japan, Netherlands, New Zealand, Russia, Spain, Taiwan, and United States of America).
Pre-assignment details
Total of 171 participants provided informed consent, of which 92 were rolled over from prior studies (CSL312\_2001 and CSL312\_3001) and 79 were treatment-naive. Of 79 participants, 2 failed screening and 77 entered the run-in period. Only 69 participants completed the run-in period. Total of 8 participants discontinued during run-in period: 1 participated less than 1 month, 5 had insufficient HAE attacks, 1 discontinued due to a laboratory abnormality, and 1 discontinued for other reason.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 42.3 Years STANDARD_DEVIATION 15.31 |
| Age, Customized <=18 years | 12 Participants |
| Age, Customized >=65 years | 15 Participants |
| Age, Customized Between 18 and 64 years | 134 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 150 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 22 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 135 Participants |
| Sex: Female, Male Female | 101 Participants |
| Sex: Female, Male Male | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 161 |
| other Total, other adverse events | 147 / 161 |
| serious Total, serious adverse events | 14 / 161 |
Outcome results
None listed