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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

CSL312 (garadacimab) in the prevention of hereditary angioedema attacks

65

Of the 64 subjects, consisting of 58 adult subjects and 6 adolescent (=< 17 years of age) subjects, with hereditary angioedema with C1-esterase inhibitor deficiency (C1-INH HAE) included in the Intent-to-treat (ITT) Analysis Set, the majority of subjects were female (38 [59.4%] subjects). Most subjects were White (55 [85.9%] subjects) and of Not Hispanic or Latino ethnicity (60 [93.8%] subjects). There were 6 (9.4%) subjects identified as Asian-Japanese, 1 (1.6%) subject identified as Black or African American, and 1 (1.6%) subject identified as Native Hawaiian or Other Pacific Islander. The mean (SD) overall age of all subjects was 41.2 (15.92) years, with subjects ranging from 12 to 69 years. Demographic characteristics of all subjects were comparable between treatment arms.

A total of 80 subjects with C1-INH HAE provided informed consent and were screened. Seventy-six subjects entered the Run-in Period. Sixty-five subjects completed the Run-in Period and were randomized (3:2 randomization scheme) to CSL312 (39 subjects) or placebo (26 subjects) in the Treatment Period. One subject in the placebo arm was randomized to blinded treatment in error, never entered the Treatment Period nor received study treatment, and therefore was not included in any post randomization analysis. Of the 64 subjects (CSL312 [39 subjects] or placebo [25 subjects]) who were randomized to blinded treatment and received the loading dose, 61 completed treatment. Three subjects, all in the placebo arm, discontinued treatment due to withdrawal by subject.

There were no deaths, adverse events of special interest (abnormal bleeding events, thromboembolic events, severe hypersensitivity including anaphylaxis), or adverse events leading to discontinuation reported during the study. One subject in the CSL312 arm experienced a severe serious adverse event (SAE) of Hereditary Angioedema which was not related to the study treatment and had an outcome of recovered / resolved. This was the only SAE reported during the study. The percentage of subjects experiencing at least 1 Treatment-emergent adverse event (TEAE) was comparable between the CSL312 arm and placebo arm (25 / 39 [64.1%] subjects and 15 / 25 [60.0%] subjects, respectively). Of the 40 subjects experiencing TEAEs during the study, all TEAEs were of mild (CSL312: 16 / 39 [41.0%] subjects; placebo: 15 / 25 [60.0%] subjects) or moderate (CSL312: 16 / 39 [41.0%] subjects; placebo: 7 / 25 [28.0%] subjects) severity, except for 1 subject in the CSL312 arm who experienced the severe SAE of Hereditary Angioedema. The most frequently reported TEAEs by preferred term in both CSL312 and placebo arms were Headache (13 events in 7 / 64 [10.9%] subjects), Upper Respiratory Tract Infection (6 events in 6 / 64 [9.4%] subjects), and Nasopharyngitis (4 events in 4 / 64 [6.3%] subjects). Two subjects in the CSL312 arm tested positive for anti-garadacimab antibodies. One of these subjects tested positive at baseline (a reciprocal titer value of 10) and no anti-garadacimab antibodies were detected at subsequent study visits. The other subject tested positive on Day 182 (titer value of 10). There was no impact observed on CSL312 pharmacokinetics, pharmacodynamics, efficacy, or safety. The following events were reported as clinically significant laboratory abnormalities reported as TEAEs: 2 events of Prothrombin fragment 1.2 increased (1 subject in the CSL312 arm [event was considered related to study treatment], and 1 subject in the placebo arm [event was not related to study treatment]); and single events of Urine leukocyte esterase positive, White blood cells urine positive, Bacterial test positive, and Urinary sediment present in 1 subject in the placebo arm (events not related to study treatment).

Primary Endpoint There was a statistically significant lower HAE attack rate in subjects receiving CSL312 compared to subjects receiving placebo (p < 0.001, 2-sided Wilcoxon Test). The mean (SD) and median (Q1, Q3) time normalized number of HAE attacks per month during the 6-month Treatment Period was 0.27 (0.683) attacks and 0.00 (0.00, 0.31) attacks in the CSL312 arm, and 2.01 (1.341) attacks and 1.35 (1.00, 3.20) attacks in the placebo arm. Secondary Endpoints The mean (SD) reduction in the time normalized number of HAE attacks during the 6-month Treatment Period compared to the Run-in Period was 90.67% (22.433) in the CSL312 arm and 20.21% (42.661) in the placebo arm (nominal p < 0.001). The mean (SD) reduction in the time normalized number of HAE attacks compared to the Run-in Period in the CSL312 arm during the first 3 months of treatment was 91.10% (21.255), and during the second 3 months of treatment was 90.12% (25.624), showing an early onset effect of treatment, which was generally maintained over time (6-month Treatment Period). During the Treatment Period, 24 / 39 (61.5%) subjects in the CSL312 arm were attack free compared with 0 subjects in the placebo arm (nominal p-value < 0.001). In the CSL312 arm, 28 / 39 (71.8%) subjects were attack-free during the first 3 months of treatment, and 27 / 39 (69.2%) subjects were attack-free during the second 3 months of treatment, showing an early onset effect of treatment, which was generally maintained over time. The number of subjects in the CSL312 arm that were attack-free (28 / 39 [71.8%] subjects) compared to placebo (2 / 24 [8.3%] subjects) in the first 3 months of treatment was statistically significant (p < 0.001, Fisher Exact Test). The mean (SD) time-normalized number of HAE attacks per month requiring on demand treatment was lower in the CSL312 arm (0.23 [0.663] attacks per month) compared to placebo (1.86 [1.412] attacks per month; nominal p < 0.001). The mean (SD) time-normalized number of moderate or severe HAE attacks per month was lower in the CSL312 arm (0.13 [0.296] attacks per month) than the placebo arm (1.35 [1.166] attacks per month; nominal p < 0.001). Subjects receiving CSL312 had a greater reduction in the time-normalized number of HAE attacks per month compared to placebo during the first (CSL312: 0.26 attacks, placebo: 1.97 attacks; nominal p < 0.001) and second (CSL312: 0.28 attacks, placebo: 1.86 attacks; nominal p < 0.001) 3 months of treatment. There was a statistically significant percentage reduction (ie, relative difference) in the means of time normalized number of HAE attacks for the 6-month Treatment Period of the CSL312 arm compared to placebo (p < 0.001, 2-sided Wilcoxon Test; 86.51% reduction). At the end of treatment (Day 182), there was a statistically significant difference (p < 0.001, Chi-squared test) in the proportion of subjects rating their response to therapy (SGART) as good or excellent among those receiving CSL312 compared to placebo. In the CSL312 arm, 81.6% rated their response to therapy as good or excellent compared to 33.3% in the placebo arm.

In subjects with C1-INH HAE, CSL312 at 200 mg administered SC once a month was safe, well tolerated, and effective for the prevention of HAE attacks during the 6-month Treatment Period. Efficacy of CSL312 was consistently observed across different efficacy endpoints. Data from the first and second 3 months of treatment showed CSL312 had an early onset treatment effect that was generally maintained over time.

Feb. 28, 2023

https://www.sciencedirect.com/science/article/abs/pii/S0140673623003501?via%3Dihub

Yes

CSL will consider requests to share Individual Patient Data (IPD) from systematic review groups or bona-fide researchers. For information on the process and requirements for submitting a voluntary data sharing request for IPD, please contact CSL at clinicaltrials@cslbehring.com. Applicable country specific privacy and other laws and regulations will be considered and may prevent sharing of IPD. If the request is approved and the researcher has executed an appropriate data sharing agreement, IPD that has been appropriately anonymized will be available. Supporting Materials: Study Protocol Statistical Analysis Plan Time Frame: IPD requests may be submitted to CSL no earlier than 12 months after publication of the results of this study via an article made available on a public website. Access Criteria: Requests may only be made by systematic review groups or bona-fide researchers whose proposed use of the IPD is non-commercial in nature and has been approved by an internal review committee. An IPD request will not be considered by CSL unless the proposed research question seeks to answer a significant and unknown medical science or patient care question as determined by CSL's internal review committee. The requesting party must execute an appropriate data sharing agreement before IPD will be made available.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210056

Akama Hideto

CSL Behring K.K.

Aoyama Building, 1-2-3 Kita-Aoyama, Minato-ku, Tokyo

JPN-CHIKEN@csl.com.au

Akama Hideto

CSL Behring K.K.

Aoyama Building, 1-2-3 Kita-Aoyama, Minato-ku, Tokyo

+81-3-4213-0191

JPN-CHIKEN@csl.com.au

Complete

Aug. 01, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

prevention purpose

Male or female >= 12 years of age; diagnosed with clinically confirmed C1-INH hereditary angioedema; experience >= 3 attacks during the 3 months before screening

Concomitant diagnosis of another form of angioedema such as idiopathic or acquired angioedema, recurrent angioedema associated with urticarial or hereditary angioedema type 3

Both

Hereditary angioedema

Subcutaneous injection of Factor XIIa antagonist monoclonal antibody (CSL312) 200 mg

Time-normalized number of HAE attacks during treatment period (up to 6 months)

1. Reduction in the HAE attack rate during the treatment period compared to the run-in period (up to 6 months)
2. Time-normalized number of attacks requiring on-demand treatment (6 months, and first 3 months and second 3 months)
3. Time-normalized number of moderate and/or severe HAE attacks (6 months, and first 3 months and second 3 months)
4. Time-normalized number of HAE attacks at various timepoints during the treatment period (first 3 months and second 3 months and 6 months)
5. Percent reduction in the time-normalized number of HAE attacks between CSL312 and Placebo (6 months, and first 3 months and second 3 months)
6. Subject's Global Assessment of Response to Therapy (SGART) (up to 6 months)
7. Number and percent of subjects with adverse events, adverse events of special interest, serious adverse events, CSL312-induced anti-CSL312 antibodies, clinically significant abnormalities in laboratory assessments (up to 8 months)

Mar. 23, 2021

Canada/Israel/Germany/Spain/Hungary/Netherland/USA/Italy