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

In spite of the growing attention to HAE patients by the medical community and
stakeholders, the burden of this disease is very high and quality of life is
still negatively impacted. Hereditary angioedema negatively impacts a patient*s
daily-life, psycho-social health, and productivity both during times of attack
and during times of remission [Aygoren-Pursun et al. 2014].

The availability of prophylactic therapies that reduce the frequency and / or
severity of attacks has improved, however there are limitations to the
treatment armament such as an unfavorable side effect profile (ie, attenuated
androgens), a lack of effect (ie, anti-fibrinolytics), or the frequency of
administration (intravenous [IV] or subcutaneous [SC] C1-INH). Furthermore,
there are currently no therapies specifically developed for
treatment or prevention of HAE attacks due to nC1-INH HAE. There remains a
medical need for effective and safe therapies that prevent and reduce the
disease burden, improve the quality of life, and offer a convenient dosing
regimen for patients with HAE [Valerieva 2018].

CSL312 may have the potential to address current unmet needs as a mAb with a
novel mechanism of action targeting FXIIa, which is elevated in the serum
during acute HAE attacks compared to normal levels observed during times of
remission [Cugno et al. 1996]. CSL312 targets FXIIa to inhibit the
kallikrein-kinin pathway, thereby inhibiting excessive production of BK, the
mediator of swelling in HAE attacks. In addition, the SC route of
administration and CSL312 may offer improved patient convenience compared to
other products registered for prevention of HAE attacks.

The primary objective of this study is to evaluate the efficacy of SC
administration of CSL312 as prophylaxis to prevent HAE attacks in subjects with
HAE.

The secondary objectives of the study are:
1. To characterize the clinical efficacy of SC CSL312 in the prophylactic
treatment of HAE.
2. To evaluate the safety of SC CSL312 in the prophylactic treatment of HAE.

This is a multicenter, double-blind, randomized, placebo-controlled,
parallel-arm, phase 3 study to investigate the efficacy and safety of CSL312
(also known as garadacimab) administered subcutaneously (SC) for the
prophylaxis to prevent HAE attacks in adolescent (12 to 17 years, inclusive)
and adult subjects with C1-esterase inhibitor (C1-INH) HAE. This study will be
conducted globally.
Following informed consent, subjects will undergo a Screening Period of up to 1
month to determine eligibility for enrollment into the study. Screened subjects
who meet all the inclusion and none of the exclusion criteria will enter a
Run-in Period to confirm the required baseline HAE attack rate of * 1 attack
per month. Subjects must complete at least 1 month of the Run-in Period.
Additionally, subjects must experience at least 2 HAE attacks during the Run-In
Period to be eligible to enter the Treatment Period. Subjects who experience at
least 2 attacks during the required first month of the
Run-In Period may enter the Treatment Period if they also meet all other
criteria as stated in Section 4.1.3 of the protocol.

Subjects who do not meet the screening criteria for entering the Run-in Period
within 30 days may be able to rescreen with confirmation from the sponsor.
Subjects who do not meet the minimum HAE attack rate during the Run-in Period
and / or all other criteria for entering the Treatment Period will be
considered Run-in failures and will not be allowed to rescreen. Eligible
subjects will be randomized 3:2 to either the CSL312
Active Arm (CSL312 SC) or the Placebo Arm. Randomization will take age (* 17
years, > 17 years) and, for adults, baseline attack rate observed during the
Run-in Period (1 to < 3 attacks / month, and * 3 attacks / month) into account.
Following the Treatment Period, subjects will either enter a 2-month Follow-up
Period (ie, 3 months after last investigational product administration) or may
roll-over into an open-label phase 3b study (CSL312_3002).

Subjects will be randomly assigned to receive one of the following treatments:
- Group 1 CSL312
- Group 2 placebo

Subjects randomized to the Active Arm will receive CSL312 SC.

Subjects randomized to the Placebo Arm will receive volume-matched placebo SC.

The subjects participation in this study will last about 7-11 months In total
the subject will visit the hospital approximately 7-9 times. Each visit will
take between 30 minutes and 2 hours to complete.
This study is divided in 4 periods; a screening visit, a run-in period, one
treatment period and a follow up period. The run-in period will last between 1
and 2 months. You will not need to come to the hospital during the run-in
period and instead run-in visits will be performed by telephone calls of
approximately 15 minutes every 15 days. Treatment with CSL312 will start after
the run-in period.
Please refer to page 11-15 of the protocol (schedule of events) for more
information.

The following tests and procedures will take place during the hospital visits
- questions are asked about the medical history, demographics and eligibility
questions
- Measurement of vital signs / physical examination (e.g. blood pressure, heart
rate, temperature and respiratory rate), height, weight
- Blood and urine samples are taken
- Pregnancy test for woman of childbearing potential
- ECG

In addition patients are asked to complete the eDiary and questionnaires.

Possible side effects that are already known are described in the
Investigator's Brochure and in paragraph 6 of the subject informed consent
form.