CSL312 (Garadacimab) in the Prevention of Hereditary Angioedema Attacks

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, double-blind, randomized, placebo-controlled, parallel-arm study to investigate the efficacy and safety of subcutaneous administration of CSL312 (garadacimab) in the prophylactic treatment of hereditary angioedema.

Official Title
-----------------
A Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-arm Study to Investigate the Efficacy and Safety of Subcutaneous Administration of CSL312 (Garadacimab) in the Prophylactic Treatment of Hereditary Angioedema

Conditions
-----------------
Hereditary Angioedema

Intervention / Treatment
-----------------
* Biological: CSL312
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female ≥ 12 years of age; diagnosed with clinically confirmed C1-INH hereditary angioedema; experience ≥ 3 attacks during the 3 months before screening. Note: For subjects taking any prophylactic HAE therapy during the 3 months before Screening, ≥ 3 HAE attacks may be documented over 3 consecutive months before commencing the prophylactic therapy. Exclusion Criteria: Concomitant diagnosis of another form of angioedema such as idiopathic or acquired angioedema, recurrent angioedema associated with urticarial or hereditary angioedema type 3

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSL312<br>Participants received a CSL312 loading dose of 400 mg as two 200 mg SC injections in Month 1 along with CSL312 of 200 mg subcutaneous (SC) injections, once monthly from Months 2 to 6. | Biological: CSL312<br>* Fully human immunoglobulin G subclass 4/lambda recombinant monoclonal antibody<br>* Other names: garadacimab;|
| Placebo Comparator: Placebo<br>Participants received a CSL312 matched loading dose of placebo as two SC injections in Month 1 along with CSL312 matched placebo SC injections, once monthly from Months 2 to 6. | Drug: Placebo<br>* Buffer without active ingredient<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-Normalized Number of Hereditary Angioedema (HAE) Attacks Per Month During Treatment Period | 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. | First injection up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in the Time-normalized Number of HAE Attacks Per Month During the Treatment Period Compared to the Run-in Period | Percentage change 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)]. Time-normalized number of HAE attacks per month during treatment period was calculated per participant as: [number of HAE attacks / length of participant treatment in days] * 30.4375. | 6 months, first 3-months and second 3-months of treatment period | 
| Time-Normalized Number of HAE Attacks Per Month Requiring On-Demand Treatment | 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 / length of participant in days] * 30.4375. | 6 months, first 3-months and second 3-months of treatment period | 
| Time-Normalized Number of Moderate or Severe HAE Attacks Per Month | 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. | 6 months, first 3-months and second 3-months of treatment period | 
| Time-normalized Number of HAE Attacks Per Month in the First 3-months and Second 3-months of Treatment Period | 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. | First 3-months and second 3-months of treatment period | 
| Relative Difference in Means in the Time-Normalized Number of HAE Attacks Per Month Between CSL312 to Placebo | Relative difference in means in the time-normalized number of HAE attacks per month CSL312 to Placebo was calculated as: 100 * [(mean time-normalized number of HAE attacks for CSL312 - mean time-normalized number of HAE attacks for placebo) / mean time-normalized number of HAE attacks for placebo]. 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. | 6 months, first 3-months and second 3-months of treatment period | 
| Percentage of Participants With a Response to Subject's Global Assessment of Response to Therapy (SGART) | SGART is a self-assessment by the participant and measures the subject's overall treatment response to the investigational product 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). | Up to 6 months | 
| Number of Participants With at Least One Adverse Event (AE), Serious Adverse Event (SAE), and AEs of Special Interest (AESI) | AE is any untoward medical occurrence in a participant administered with an investigational product which does not necessarily have a causal relationship with treatment, can be any unfavorable and unintended sign, symptom, or disease temporally associated with use of an investigational product, whether or not considered related to product. SAE is any untoward medical occurrence that results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, is a congenital anomaly or birth defect, or is a medically significant event. An AESI is an AE of scientific and medical concern specific to sponsor's product or program, for which ongoing monitoring and rapid communication by investigator to sponsor is appropriate. | From first dose of study drug up to 3 months after the last injection (approximately 8 months) | 
| Number of Participants With CSL312-induced Anti-CSL312 Antibodies |  | Up to 8 months | 
| Number of Participants With Clinically Significant Abnormalities in Laboratory Assessments Reported as Treatment Emergent Adverse Events (TEAEs) | Laboratory assessments included: Hematology, biochemistry, urinalysis, and coagulation parameters. | From first dose of study drug up to 3 months after the last injection (approximately 8 months) | 
| Percentage of Participants With at Least One AE, SAE, and AESI | AE is any untoward medical occurrence in a participant administered with an investigational product which does not necessarily have a causal relationship with treatment, can be any unfavorable and unintended sign, symptom, or disease temporally associated with use of an investigational product, whether or not considered related to product. SAE is any untoward medical occurrence that results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, is a congenital anomaly or birth defect, or is a medically significant event. An AESI is an AE of scientific and medical concern specific to sponsor's product or program, for which ongoing monitoring and rapid communication by investigator to sponsor is appropriate. | From first dose of study drug up to 3 months after the last injection (approximately 8 months) | 
| Percentage of Participants With CSL312-induced Anti-CSL312 Antibodies |  | Up to 6 months | 
| Percentage of Participants With Clinically Significant Abnormalities in Laboratory Assessments Reported as TEAEs | Laboratory assessments included: Hematology, biochemistry, urinalysis, and coagulation parameters. | From first dose of study drug up to 3 months after the last injection (approximately 8 months) |