Trial Outcomes & Findings for Study of BCX7353 as a Treatment for Attacks of Hereditary Angioedema (NCT NCT03240133)

NCT ID: NCT03240133

Last Updated: 2021-04-01

Results Overview

Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack, where zero indicated no pain or swelling and 100 mm indicated worst possible pain or swelling. Subjects completed the VAS immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 \& at 24 hours post-dose. The primary endpoint was the proportion of subject attacks with an improved or stable 3-symptom composite VAS score at 4 hours post dose. The 3-symptom composite was calculated as the average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject was considered improved or stable if the change from baseline (CFB; time of drug administration) in VAS was ≤ 0.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 58 participants
• Primary outcome timeframe: Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose
• Results posted on: 2021-04-01

Participant Flow

HAE subjects attended a Screening Visit up to 35 days before the baseline visit, for assessment of eligibility to participate in the study.

Participant milestones

Measure	Part 1: Berotralstat (750 mg) & Placebo Treated HAE Attacks Each subject treated 3 HAE attacks, 1 with placebo and 2 with 750 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.	Part 2: Berotralstat (500 mg) & Placebo Treated HAE Attacks Each subject treated 3 HAE attacks, 1 with placebo and 2 with 500 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.	Part 3: Berotralstat (250 mg) & Placebo Treated HAE Attacks Each subject treated 3 HAE attacks, 1 with placebo and 2 with 250 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.
Overall Study STARTED	33	14	11
Overall Study Completed Period 1	33	14	11
Overall Study Completed Period 2	32	11	11
Overall Study Completed Period 3	30	11	11
Overall Study COMPLETED	30	11	10
Overall Study NOT COMPLETED	3	3	1

Reasons for withdrawal

Measure	Part 1: Berotralstat (750 mg) & Placebo Treated HAE Attacks Each subject treated 3 HAE attacks, 1 with placebo and 2 with 750 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.	Part 2: Berotralstat (500 mg) & Placebo Treated HAE Attacks Each subject treated 3 HAE attacks, 1 with placebo and 2 with 500 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.	Part 3: Berotralstat (250 mg) & Placebo Treated HAE Attacks Each subject treated 3 HAE attacks, 1 with placebo and 2 with 250 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.
Overall Study Withdrawal by Subject	0	1	0
Overall Study Adverse Event	1	1	0
Overall Study Rash	1	0	0
Overall Study sponsor closure/completion of Part 1 of the study	1	0	0
Overall Study Intercurrent illness.	0	1	0
Overall Study Sponsor/competent authority/IRB/IEC discontinuation	0	0	1

Baseline Characteristics

Study of BCX7353 as a Treatment for Attacks of Hereditary Angioedema

Baseline characteristics by cohort

Measure	Part 1: Berotralstat (750 mg) & Placebo Treated HAE Attacks n=33 Participants Each subject treated 3 HAE attacks, 1 with placebo and 2 with 750 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.	Part 2: Berotralstat (500 mg) & Placebo Treated HAE Attacks n=14 Participants Each subject treated 3 HAE attacks, 1 with placebo and 2 with 500 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.	Part 3: Berotralstat (250 mg) & Placebo Treated HAE Attacks n=11 Participants Each subject treated 3 HAE attacks, 1 with placebo and 2 with 250 mg berotralstat. Placebo vs berotralstat treatment of an HAE attack was assigned by randomization.	Total n=58 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	32 Participants n=5 Participants	14 Participants n=7 Participants	11 Participants n=5 Participants	57 Participants n=4 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Age, Continuous	43.7 years STANDARD_DEVIATION 12.5 • n=5 Participants	42.1 years STANDARD_DEVIATION 10.5 • n=7 Participants	34.9 years STANDARD_DEVIATION 10.9 • n=5 Participants	41.6 years STANDARD_DEVIATION 12.0 • n=4 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	11 Participants n=7 Participants	7 Participants n=5 Participants	35 Participants n=4 Participants
Sex: Female, Male Male	16 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	23 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	33 Participants n=5 Participants	14 Participants n=7 Participants	11 Participants n=5 Participants	58 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment Austria	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Region of Enrollment Romania	4 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	4 participants n=4 Participants
Region of Enrollment Hungary	2 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants
Region of Enrollment Denmark	3 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	3 participants n=4 Participants
Region of Enrollment North Macedonia	2 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants
Region of Enrollment Poland	2 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants	6 participants n=4 Participants
Region of Enrollment Italy	3 participants n=5 Participants	4 participants n=7 Participants	2 participants n=5 Participants	9 participants n=4 Participants
Region of Enrollment United Kingdom	6 participants n=5 Participants	5 participants n=7 Participants	2 participants n=5 Participants	13 participants n=4 Participants
Region of Enrollment Israel	4 participants n=5 Participants	2 participants n=7 Participants	0 participants n=5 Participants	6 participants n=4 Participants
Region of Enrollment France	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Region of Enrollment Switzerland	2 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants
Region of Enrollment Germany	3 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants	9 participants n=4 Participants
Adjusted qualifying HAE attack rate	3.08 HAE attacks/month STANDARD_DEVIATION 1.40 • n=5 Participants	3.03 HAE attacks/month STANDARD_DEVIATION 1.23 • n=7 Participants	3.23 HAE attacks/month STANDARD_DEVIATION 1.82 • n=5 Participants	3.09 HAE attacks/month STANDARD_DEVIATION 1.42 • n=4 Participants

PRIMARY outcome

Timeframe: Mean composite VAS for HAE attack symptoms severity prior to IMP treatment and 4 hours post-dose

Population: The number of participants analyzed in each analysis set corresponds to number of HAE attacks treated with placebo or berotralstat.

Subjects completed a 3-component VAS on a 100 mm scale for severity of abdominal pain, skin pain and skin swelling associated with the HAE attack, where zero indicated no pain or swelling and 100 mm indicated worst possible pain or swelling. Subjects completed the VAS immediately prior to study drug administration, then at 1, 2, 3, 4, approximately 8 & at 24 hours post-dose. The primary endpoint was the proportion of subject attacks with an improved or stable 3-symptom composite VAS score at 4 hours post dose. The 3-symptom composite was calculated as the average of the VAS scores for abdominal pain, skin pain, and skin swelling. A subject was considered improved or stable if the change from baseline (CFB; time of drug administration) in VAS was ≤ 0.

Outcome measures

Measure	Part 1: Berotralstat 750 mg - Predose n=59 HAE Attacks HAE attack prior to dosing with 750mg berotralstat	Part 1: Placebo - Pre-dose n=28 HAE Attacks HAE attack prior to dosing with placebo	Part 1: Berotralstat 750 mg - 4hr Post-dose n=59 HAE Attacks HAE attack 4 hr post dosing with 750mg berotralstat	Part 1: Placebo - 4hr Post-dose n=28 HAE Attacks HAE attack 4 hr post dosing with placebo	Part 2: Berotralstat 500 mg - Predose n=24 HAE Attacks HAE attack prior to dosing with 500mg berotralstat	Part 2: Placebo - Pre-dose n=9 HAE Attacks HAE attack prior to dosing with placebo	Part 2: Berotralstat 500 mg - 4hr Post-dose n=24 HAE Attacks HAE attack 4 hr post dosing with 50mg berotralstat	Part 2: Placebo - 4hr Post-dose n=9 HAE Attacks HAE attack 4 hr post dosing with placebo	Part 3: Berotralstat 250 mg - Predose n=21 HAE Attacks HAE attack prior to dosing with 250mg berotralstat	Part 3: Placebo - Pre-dose n=11 HAE Attacks HAE attack prior to dosing with placebo	Part 3: Berotralstat 250 mg - 4hr Post-dose n=21 HAE Attacks HAE attack 4 hr post dosing with 250mg berotralstat	Part 3: Placebo - 4hr Post-dose n=11 HAE Attacks HAE attack 4 hr post dosing with placebo
Proportion of Subjects With Improved or Stable Composite Visual Analog Scale (VAS) Score	13.96 VAS score - millimeters Standard Deviation 9.84	15.04 VAS score - millimeters Standard Deviation 11.90	10.54 VAS score - millimeters Standard Deviation 11.39	18.42 VAS score - millimeters Standard Deviation 14.19	17.69 VAS score - millimeters Standard Deviation 15.25	13.48 VAS score - millimeters Standard Deviation 16.11	11.31 VAS score - millimeters Standard Deviation 15.75	9.26 VAS score - millimeters Standard Deviation 11.53	14.57 VAS score - millimeters Standard Deviation 11.78	11.33 VAS score - millimeters Standard Deviation 10.17	10.92 VAS score - millimeters Standard Deviation 10.31	9.21 VAS score - millimeters Standard Deviation 9.67

PRIMARY outcome

Timeframe: 24 hours

The proportion of attacks for which subjects took SOC-Rx in the 24 hours following treatment with study drug. HAE Rescue Medications included C1-INH (Berinert, Cinryze, Ruconest) and Firazyr/Icatibant.

Outcome measures

Measure	Part 1: Berotralstat 750 mg - Predose n=59 HAE Attacks HAE attack prior to dosing with 750mg berotralstat	Part 1: Placebo - Pre-dose n=28 HAE Attacks HAE attack prior to dosing with placebo	Part 1: Berotralstat 750 mg - 4hr Post-dose n=24 HAE Attacks HAE attack 4 hr post dosing with 750mg berotralstat	Part 1: Placebo - 4hr Post-dose n=9 HAE Attacks HAE attack 4 hr post dosing with placebo	Part 2: Berotralstat 500 mg - Predose n=21 HAE Attacks HAE attack prior to dosing with 500mg berotralstat	Part 2: Placebo - Pre-dose n=11 HAE Attacks HAE attack prior to dosing with placebo	Part 2: Berotralstat 500 mg - 4hr Post-dose HAE attack 4 hr post dosing with 50mg berotralstat	Part 2: Placebo - 4hr Post-dose HAE attack 4 hr post dosing with placebo	Part 3: Berotralstat 250 mg - Predose HAE attack prior to dosing with 250mg berotralstat	Part 3: Placebo - Pre-dose HAE attack prior to dosing with placebo	Part 3: Berotralstat 250 mg - 4hr Post-dose HAE attack 4 hr post dosing with 250mg berotralstat	Part 3: Placebo - 4hr Post-dose HAE attack 4 hr post dosing with placebo
Percentage of Attacks Treated With Standard of Care Acute Attack Medication (SOC-Rx) Through 24 Hours	29.7 Percentage attacks treated with SOC-Rx	61.3 Percentage attacks treated with SOC-Rx	32.0 Percentage attacks treated with SOC-Rx	45.5 Percentage attacks treated with SOC-Rx	38.1 Percentage attacks treated with SOC-Rx	45.5 Percentage attacks treated with SOC-Rx	—	—	—	—	—	—

Adverse Events

Part1: Berotralstat 750 mg

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Part 2: Berotralstat 500 mg

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Part 3: Berotralstat 250 mg

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Parts 1, 2 and 3: Placebo

Serious events: 1 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Measure	Part1: Berotralstat 750 mg n=33 participants at risk Berotralstat : oral liquid formulation	Part 2: Berotralstat 500 mg n=14 participants at risk Berotralstat: oral liquid formulation	Part 3: Berotralstat 250 mg n=11 participants at risk Berotralstat: oral liquid formulation	Parts 1, 2 and 3: Placebo n=53 participants at risk Placebo: oral liquid formulation to match Berotralstat
Injury, poisoning and procedural complications kidney contusion	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Injury, poisoning and procedural complications Ligament sprain	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.

Other adverse events

Measure	Part1: Berotralstat 750 mg n=33 participants at risk Berotralstat : oral liquid formulation	Part 2: Berotralstat 500 mg n=14 participants at risk Berotralstat: oral liquid formulation	Part 3: Berotralstat 250 mg n=11 participants at risk Berotralstat: oral liquid formulation	Parts 1, 2 and 3: Placebo n=53 participants at risk Placebo: oral liquid formulation to match Berotralstat
Injury, poisoning and procedural complications Arthropod bite	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Injury, poisoning and procedural complications Fall	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Injury, poisoning and procedural complications Limb injury	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	18.2% 2/11 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Dysplastic naevus	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Nervous system disorders Dysgeusia	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
General disorders Pyrexia	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
General disorders Vessel puncture site reaction	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
General disorders Fatigue	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Gastrointestinal disorders Abdominal discomfort	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Gastrointestinal disorders Faeces discoloured	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Gastrointestinal disorders Abdominal pain	3.0% 1/33 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	14.3% 2/14 • Number of events 3 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Gastrointestinal disorders Diarrhoea	9.1% 3/33 • Number of events 3 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	14.3% 2/14 • Number of events 3 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	3.8% 2/53 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Gastrointestinal disorders Nausea	6.1% 2/33 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	14.3% 2/14 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Gastrointestinal disorders Epigastric discomfort	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Gastrointestinal disorders Vomiting	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Infections and infestations Nasopharyngitis	12.1% 4/33 • Number of events 4 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Infections and infestations Rhinitis	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	9.1% 1/11 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	3.8% 2/53 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Infections and infestations Sinusitis	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	18.2% 2/11 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Infections and infestations Upper respiratory tract infection	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	7.1% 1/14 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Infections and infestations Contusion	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	18.2% 2/11 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/53 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Injury, poisoning and procedural complications Muscle contusion	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Investigations Blood creatine phosphokinase increased	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	3.8% 2/53 • Number of events 2 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Hepatobiliary disorders Cholelithiasis	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Infections and infestations Infection	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.
Infections and infestations Urinary tract infection	0.00% 0/33 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/14 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	0.00% 0/11 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.	1.9% 1/53 • Number of events 1 • Adverse events (AEs) were collected from informed consent signature until 16 to 19 days after the 3rd or final HAE attack treated with IMP. As the HAE attack frequency varied between subjects, subject duration of study participation and therefore the duration over which AEs were collected was dependent on attack frequency and therefore variable. The maximum period over which AEs were collected was 281 days. AEs were assigned to an attack treated with placebo or berotralstat depending on which IMP was used most recently prior to AE onset. HAE attacks and their associated symptoms were not defined as AEs, unless they met the criteria for an SAE.

Additional Information

Study Director

BioCryst Pharmaceuticals Inc

Phone: +1 919-859-1302

Email: clinicaltrials@biocryst.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place