Trial Outcomes & Findings for Study to Evaluate the Clinical Efficacy and Safety of Subcutaneously Administered C1 Esterase Inhibitor for the Prevention of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema (NCT NCT02584959)

NCT ID: NCT02584959

Last Updated: 2021-06-08

Results Overview

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-normalized number of angioedema attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4 \* (number of attacks during treatment period) / (days of treatment period).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 75 participants
• Primary outcome timeframe: Weeks 1 to 14 for treatment period 1 and 2
• Results posted on: 2021-06-08

Participant Flow

This was a multicenter study conducted at 33 sites/centers in 7 countries: United States, Canada , Germany, Hungary, Israel, Spain, and Romania .

Of the 81 participants screened, 6 subjects failed to meet the randomization criteria and were not randomly assigned to a treatment sequence . All 75 randomly assigned participants received at least 1 dose of the IP.

Participant milestones

Measure	Experimental/Placebo Participants were randomized to receive C1 Esterase Inhibitor in the 1st treatment period and then switched to Placebo in the 2nd treatment period.	Placebo/Experimental Participants were randomized to receive placebo treatment in the 1st treatment period and then switched to receive C1 Esterase Inhibitor in the 2nd treatment period.	Experimental/ Experimental Participants were randomized to receive C1 Esterase Inhibitor in both 1st as well as the 2nd treatment period.
Period 1 STARTED	31	29	15
Period 1 COMPLETED	28	25	15
Period 1 NOT COMPLETED	3	4	0
Period 2 STARTED	28	25	15
Period 2 COMPLETED	22	24	13
Period 2 NOT COMPLETED	6	1	2

Reasons for withdrawal

Measure	Experimental/Placebo Participants were randomized to receive C1 Esterase Inhibitor in the 1st treatment period and then switched to Placebo in the 2nd treatment period.	Placebo/Experimental Participants were randomized to receive placebo treatment in the 1st treatment period and then switched to receive C1 Esterase Inhibitor in the 2nd treatment period.	Experimental/ Experimental Participants were randomized to receive C1 Esterase Inhibitor in both 1st as well as the 2nd treatment period.
Period 1 Withdrawn from study	3	4	0
Period 2 Withdrawn from study	6	1	2

Baseline Characteristics

Study to Evaluate the Clinical Efficacy and Safety of Subcutaneously Administered C1 Esterase Inhibitor for the Prevention of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema

Baseline characteristics by cohort

Measure	Experimental/Placebo n=31 Participants Subjects will be randomized to receive C1 Esterase Inhibitor in the 1st Treatment period and then switch to Placebo in the 2nd treatment period.	Placebo/Experimental n=29 Participants Subjects will be randomized to receive a placebo treatment in the 1st Treatment period and then switch to receive C1 Esterase Inhibitor in the 2nd treatment period.	Experimental/ Experimental n=15 Participants Subjects will be randomized and receive C1 Esterase Inhibitor in both 1st as well as the 2nd treatment period	Total n=75 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	30 Participants n=5 Participants	25 Participants n=7 Participants	13 Participants n=5 Participants	68 Participants n=4 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants
Age, Continuous	40.5 years STANDARD_DEVIATION 13.16 • n=5 Participants	40.7 years STANDARD_DEVIATION 15.34 • n=7 Participants	44.4 years STANDARD_DEVIATION 16.40 • n=5 Participants	41.3 years STANDARD_DEVIATION 14.58 • n=4 Participants
Sex: Female, Male Female	23 Participants n=5 Participants	21 Participants n=7 Participants	8 Participants n=5 Participants	52 Participants n=4 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	8 Participants n=7 Participants	7 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	1 Participants n=7 Participants	0 Participants n=5 Participants	1 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	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	30 Participants n=5 Participants	27 Participants n=7 Participants	15 Participants n=5 Participants	72 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

PRIMARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Population: Data were not collected for the Experimental/Experimental Arm for this outcome measure and this represents the full analysis set.

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-normalized number of angioedema attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4 * (number of attacks during treatment period) / (days of treatment period).

Outcome measures

Measure	Treatment C1 INH n=56 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=57 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Time-Normalized Number of Attacks (NNA) for Participants During a Treatment Period	1.611 Number of attacks Interval 1.067 to 2.156	3.931 Number of attacks Interval 3.391 to 4.471	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Population: Analysis done on participants from the crossover sequences (Experimental/Placebo, Placebo/Experimental) who were dosed in both treatment periods. As the measure is implicitly a within subject comparison of the two arms the full analysis set is reported here. Participants with 0 attacks in the placebo period were excluded as %-reduct. not calculated

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA = 30.4 x (number of attacks during treatment period) / (days of treatment period).

Outcome measures

Measure	Treatment C1 INH n=49 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Proportion of Participants Meeting at Least a 50% Reduction in NNA (Normalized Number of Angioedema Attacks) During the Experimental Injection Treatment Period Relative to the Placebo Period.	38 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 3 to 14 for treatment period 1 and 2

Population: Data were not collected for the Experimental/Experimental Arm for this outcome measure and this represents the full analysis set.

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-normalized number of angioedema attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4 * (number of attacks during treatment period) / (days of treatment period).

Outcome measures

Measure	Treatment C1 INH n=55 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=55 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Time-Normalized Number of Attacks (NNA) for Participants During Each Treatment Period Excluding the First 2 Weeks.	1.524 Number of Attacks Interval 0.912 to 2.136	3.847 Number of Attacks Interval 3.237 to 4.457	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 3 to 14 for treatment period 1 and 2

Population: Analysis done on participants from the crossover sequences (Experimental/Placebo, Placebo/Experimental) who were dosed in both treatment periods. As the measure is implicitly a within subject comparison of the two arms the full analysis set is reported here. Participants with 0 attacks in the placebo period were excluded as %-reduct. not calculated

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA = 30.4 x (number of attacks during treatment period) / (days of treatment period).

Outcome measures

Measure	Treatment C1 INH n=47 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Proportion of Participants Meeting at Least a 50% Reduction in NNA (Normalized Number of Angioedema Attacks) During the Experimental Injection Treatment Period Relative to the Placebo Period Excluding the First 2 Weeks of Each Treatment Period.	36 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Population: Full analysis set from the crossover sequences (Experimental/Placebo arm and Placebo/Experimental arm) was used for analysis of this outcome measure.Participants with zero attacks in the placebo period were excluded because a percent reduction could not be calculated. Analysis was done on participants with pretreatment and post-treatment NNA values

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA = 30.4 x (number of attacks during treatment period) / (days of treatment period).

Outcome measures

Measure	Treatment C1 INH n=53 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=55 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Proportion of Participants Meeting at Least a 50% Reduction in NNA (Normalized Number of Angioedema Attacks) During the Experimental Injection Treatment Period Relative to the Pre-treatment Assessment.	41 Participants	13 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Population: Data were not collected for the Experimental/Experimental Arm for this outcome measure and this represents the full analysis set.

Severity of the angioedema attack sign/symptom was characterized as None: no symptom; Mild: noticeable symptom but easily tolerated by the participant and did not interfere with routine activities; Moderate: symptom interfered with the participant's ability to attend school or participate in family life and social/recreational activities; Severe: symptom significantly limited the participant's ability to attend school or participate in family life and social/recreational activities. Symptom severity score was assigned as Mild = 1, Moderate = 2 and Severe = 3. Cumulative attack severity score was the sum of the maximum symptom severity scores recorded for each angioedema attack in a treatment period. Cumulative attack-severity score normalized per month [(raw score/number of days of participation in that treatment period)*30.4] was reported here. Cumulative attack-severity score normalized per month ranged from 0 to 19.83 and higher scores represent worse symptoms.

Outcome measures

Measure	Treatment C1 INH n=56 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=57 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Cumulative Attack Severity	3.159 Score on a scale Interval 1.856 to 4.463	8.041 Score on a scale Interval 6.746 to 9.336	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Population: Data were not collected for the Experimental/Experimental Arm for this outcome measure and this represents the full analysis set.

Attack free days were normalized per month.

Outcome measures

Measure	Treatment C1 INH n=56 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=57 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Number of Attack-free Days	26.788 Days Interval 25.106 to 28.47	21.353 Days Interval 19.681 to 23.025	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Population: Data were not collected for the Experimental/Experimental Arm for this outcome measure and this represents the full analysis set.

Angioedema attacks were normalized per month.

Outcome measures

Measure	Treatment C1 INH n=56 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=57 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Number of Angioedema Attacks Requiring Acute Treatment	1.454 Number of attacks Interval 0.906 to 2.002	3.628 Number of attacks Interval 3.085 to 4.172	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Population: For treatment with C1 INH (Overall treatment with C1 INH group) all participants who received C1 INH in each of the randomized arms (experimental/placebo, placebo/experimental and experimental/experimental) are included.

The number of Acute Hereditary Angioedema Attacks that required Icatibant as acute therapy is presented by the number of Icatibant injections.

Outcome measures

Measure	Treatment C1 INH n=181 Attacks requiring Icatibant Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=453 Attacks requiring Icatibant Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Response to Icatibant When Administered for an Acute Attack requiring 1 injection	129 Attacks requiring Icatibant	306 Attacks requiring Icatibant	—	—	—	—
Response to Icatibant When Administered for an Acute Attack requiring 3 injections	13 Attacks requiring Icatibant	30 Attacks requiring Icatibant	—	—	—	—
Response to Icatibant When Administered for an Acute Attack requiring >= 4 injections	1 Attacks requiring Icatibant	28 Attacks requiring Icatibant	—	—	—	—
Response to Icatibant When Administered for an Acute Attack requiring 2 injections	38 Attacks requiring Icatibant	89 Attacks requiring Icatibant	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Treatment-emergent adverse events (TEAE) were counted by the treatment most recently taken when the event occurred. Participants were counted once per category per treatment.

Outcome measures

Measure	Treatment C1 INH n=71 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=57 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Number of Patients With Adverse Events (AEs) Any TEAE	42 Participants	32 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Serious TEAE	2 Participants	3 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Severe TEAE	4 Participants	3 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Treatment-related SAE within 24 hrs of IP admin.	0 Participants	0 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) TEAE within 24 hrs IP admin. leading to withdrawal	1 Participants	0 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Deaths due to TEAE	0 Participants	0 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Hospitalizations due to TEAE	2 Participants	3 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) TEAE within 24 hours of IP administration	10 Participants	7 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Serious TEAE within 24 hours of IP administration	0 Participants	0 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Treatment-related TEAE within 24 hrs of IP admin.	3 Participants	2 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) TEAE leading to withdrawal	1 Participants	2 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Treatment-related TEAE	5 Participants	4 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Treatment-related SAE	0 Participants	0 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Treatment-related severe TEAE	0 Participants	0 Participants	—	—	—	—
Number of Patients With Adverse Events (AEs) Treatment-related TEAE leading to withdrawal	1 Participants	0 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Injection site reactions (Erythema, Swelling, Cutaneous pain, Burning sensation, Itching/Pruritus, Warm sensation) were recorded on a designated eCRF page by the site personnel who monitored the local reaction for 1 hour after IP administration 5 times during each treatment period.

Outcome measures

Measure	Treatment C1 INH n=71 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=57 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Number of Participants With Injection Site Reactions Any injection site reaction	42 Participants	15 Participants	—	—	—	—
Number of Participants With Injection Site Reactions Any severe injection site reaction	2 Participants	0 Participants	—	—	—	—
Number of Participants With Injection Site Reactions Any moderate injection site reaction	14 Participants	1 Participants	—	—	—	—
Number of Participants With Injection Site Reactions Any mild injection site reaction	42 Participants	15 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Anti-C1 INH antibodies were measured during study time.

Outcome measures

Measure	Treatment C1 INH n=71 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=57 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Number of Patients With Positive Anti-C1 INH Antibodies Positive anti-C1 INH antibodies prior treatment	0 Participants	0 Participants	—	—	—	—
Number of Patients With Positive Anti-C1 INH Antibodies Positive anti-C1 INH antibodies developed	0 Participants	0 Participants	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable.

AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau).

Outcome measures

Measure	Treatment C1 INH n=6 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=3 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: AUC (0-96) and AUC (0-t) for Functional C1 INH Binding Activity AUC (0-96)	31070 mU*h/mL Standard Deviation 17396	13860 mU*h/mL Standard Deviation 7269.0	—	—	—	—
PK Parameters: AUC (0-96) and AUC (0-t) for Functional C1 INH Binding Activity AUC (0-t)	31190 mU*h/mL Standard Deviation 17389	13860 mU*h/mL Standard Deviation 7268.3	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable.

AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau).

Outcome measures

Measure	Treatment C1 INH n=6 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=3 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: AUC (0-96) and AUC (0-t) for C1 INH Antigen Concentrations AUC (0-96)	6882 mcg*h/mL Standard Deviation 4586.0	1849 mcg*h/mL Standard Deviation 426.36	—	—	—	—
PK Parameters: AUC (0-96) and AUC (0-t) for C1 INH Antigen Concentrations AUC (0-t)	6902 mcg*h/mL Standard Deviation 4574.0	1849 mcg*h/mL Standard Deviation 426.09	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable.

AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau).

Outcome measures

Measure	Treatment C1 INH n=5 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treamtment C1 INH) AUC (0-96)	16690 mg*h/L Standard Deviation 803.60	—	—	—	—	—
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treamtment C1 INH) AUC (0-t)	16780 mg*h/L Standard Deviation 895.63	—	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable. No summary analysis was done and participant wise data are reported.

AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau). Participant wise data was reported for this outcome.

Outcome measures

Measure	Treatment C1 INH n=2 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treatment Placebo) AUC (0-t) - Participant 2	2150 mg*h/L	—	—	—	—	—
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treatment Placebo) AUC (0-96) - Participant 1	8840 mg*h/L	—	—	—	—	—
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treatment Placebo) AUC (0-96) - Participant 2	2150 mg*h/L	—	—	—	—	—
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treatment Placebo) AUC (0-t) - Participant 1	8840 mg*h/L	—	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable.

Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration

Outcome measures

Measure	Treatment C1 INH n=6 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=3 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: Cmax and Cmin for Functional C1 INH Binding Activity Cmax	396.20 mU/mL Standard Deviation 273.013	159.50 mU/mL Standard Deviation 82.982	—	—	—	—
PK Parameters: Cmax and Cmin for Functional C1 INH Binding Activity Cmin	258.15 mU/mL Standard Deviation 138.232	125.90 mU/mL Standard Deviation 62.329	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable.

Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration

Outcome measures

Measure	Treatment C1 INH n=6 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=3 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: Cmax and Cmin for C1 INH Antigen Concentrations Cmax	77.680 µg/mL Standard Deviation 52.4375	21.257 µg/mL Standard Deviation 5.1647	—	—	—	—
PK Parameters: Cmax and Cmin for C1 INH Antigen Concentrations Cmin	65.562 µg/mL Standard Deviation 45.9331	17.913 µg/mL Standard Deviation 4.4316	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable.

Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration

Outcome measures

Measure	Treatment C1 INH n=5 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment C1 INH) Cmax	200 mg/L Standard Deviation 30.82	—	—	—	—	—
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment C1 INH) Cmin	158 mg/L Standard Deviation 13.04	—	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable. No summary analysis was done and participant wise data are reported.

Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration. Participant wise data was reported for this outcome.

Outcome measures

Measure	Treatment C1 INH n=2 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment Placebo) Cmax - Participant 1	120 mg/L	—	—	—	—	—
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment Placebo) Cmax - Participant 2	27 mg/L	—	—	—	—	—
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment Placebo) Cmin - Participant 1	82 mg/L	—	—	—	—	—
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment Placebo) Cmin - Participant 2	18 mg/L	—	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable. For Complement C4 Concentration no summary analysis was done for participants in the placebo group and participant wise data for 2 participants are reported in Outcome measure #19.

tmax=time of maximum observed plasma concentration

Outcome measures

Measure	Treatment C1 INH n=6 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=3 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: Tmax Functional C1 INH Binding Activity	31.597 hours Standard Deviation 12.7038	55.689 hours Standard Deviation 49.4851	—	—	—	—
PK Parameters: Tmax C1 INH Antigen Concentration	31.656 hours Standard Deviation 24.6912	47.578 hours Standard Deviation 47.3106	—	—	—	—
PK Parameters: Tmax Complement C4 Concentration	33.417 hours Standard Deviation 36.5183	—	—	—	—	—

SECONDARY outcome

Timeframe: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2.

Population: All participants included who have taken at least one dose of investigational product and for whom the primary PK data are considered sufficient and interpretable. No summary analysis was done and participant wise data are reported.

tmax=time of maximum observed plasma concentration. Participant wise data was reported for this outcome.

Outcome measures

Measure	Treatment C1 INH n=2 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
PK Parameters: Tmax for Complement C4 Concentrations (Placebo Group) tmax - Participant 1	94.62 mg/L	—	—	—	—	—
PK Parameters: Tmax for Complement C4 Concentrations (Placebo Group) tmax - Participant 2	48.12 mg/L	—	—	—	—	—

SECONDARY outcome

Timeframe: Weeks 1 to 14 for treatment period 1 and 2

Population: Data were not collected for the Experimental/Experimental Arm for this outcome measure and this represents the full analysis set.

Disease activity was measured using a 98-day Angioedema Activity Score (AAS). The AAS collects information of disease activity in the last 24 hours. The following items are assessed: experience of swelling, severity of the swelling, timing of the swelling, extent of discomfort due to the swelling, extent that the swelling caused limitations in daily life, and feelings of being disfigured by the swelling. The instrument uses a binary response option for the first item and a three-point response scale for the 5 items thereafter. The daily AAS was the sum of the AAS items per day. Total daily ASS scores range between 0 and 15 points. Higher values stand for higher disease activity. The normalized 98-day AAS per month for a participant is calculated by (the sum of daily AAS within a treatment period/the number of days that a subject has AAS records within the treatment period)*30.4.

Outcome measures

Measure	Treatment C1 INH n=56 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=57 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Assess Disease Activity as Measured by the Angioedema Activity Score (AAS) Normalized Per Month	25.433 Score on a scale Interval 11.204 to 39.662	57.168 Score on a scale Interval 43.01 to 71.326	—	—	—	—

SECONDARY outcome

Timeframe: Week 14 for treatment period 1 and 2

Population: Visit 28b summarizes only treatment period 2 of the Experimental/Experimental arm. Therefore no participants were analyzed in the placebo group.

Self-administration survey with questions about the overall experience with the syringe was assessed in week 14 (visit 28 and 28b). Visit 28 summarizes treatment period 1 of the experimental/experimental arm and treatment periods 1 and 2 of the experimental/placebo arm and the placebo/experimental arm. Visit 28b summarizes treatment period 2 of the experimental/experimental arm.

Outcome measures

Measure	Treatment C1 INH n=59 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=40 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Participant Experience With Self-administration: Overall Experience With the Syringe Visit 28: Easy to use	48 Participants	36 Participants	—	—	—	—
Participant Experience With Self-administration: Overall Experience With the Syringe Visiti 28: Difficult to use	0 Participants	0 Participants	—	—	—	—
Participant Experience With Self-administration: Overall Experience With the Syringe Visiti 28b: Difficult to use	0 Participants	—	—	—	—	—
Participant Experience With Self-administration: Overall Experience With the Syringe Visit 28: Somewhat difficult to use	11 Participants	4 Participants	—	—	—	—
Participant Experience With Self-administration: Overall Experience With the Syringe Visit 28b: Easy to use	11 Participants	—	—	—	—	—
Participant Experience With Self-administration: Overall Experience With the Syringe Visit 28b: Somewhat difficult to use	1 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: Week 14 for treatment period 1 and 2

Population: Visit 28b summarizes only treatment period 2 of the Experimental/Experimental arm. Therefore no participants were analyzed in the placebo group.

The self-administration survey includes the number of visits needed for participants to be able to self-administer investigational product with confidence and all participants could self-administer without supervision. Visit 28 summarizes treatment period 1 of the experimental/experimental arm and treatment periods 1 and 2 of the experimental/placebo arm and the placebo/experimental arm. Visit 28b summarizes treatment period 2 of the experimental/experimental arm.

Outcome measures

Measure	Treatment C1 INH n=59 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=40 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Participant Experience With Self-administration: How Many Visits for Confidence With Self-administration Visit 28	1.8 Number of visits Standard Deviation 1.70	2.0 Number of visits Standard Deviation 2.49	—	—	—	—
Participant Experience With Self-administration: How Many Visits for Confidence With Self-administration Visit 28b	1.8 Number of visits Standard Deviation 1.22	—	—	—	—	—

SECONDARY outcome

Timeframe: Week 14 for treatment period 1 and 2

Population: Visit 28b summarizes only treatment period 2 of the Experimental/Experimental arm. Therefore no participants were analyzed in the placebo group.

The self-administration survey includes the number of visits needed for participants to be able to self-administer investigational product with confidence and all participants could self-administer without supervision. Visit 28 summarizes treatment period 1 of the experimental/experimental arm and treatment periods 1 and 2 of the experimental/placebo arm and the placebo/experimental arm. Visit 28b summarizes treatment period 2 of the experimental/experimental arm.

Outcome measures

Measure	Treatment C1 INH n=59 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=40 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28: IV better long term option	2 Participants	1 Participants	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28: SC preferred administration	56 Participants	40 Participants	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28: IV preferred administration	3 Participants	0 Participants	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28b: IV preferred administration	1 Participants	—	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28: SC better long term option	57 Participants	39 Participants	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28: Preference for admin - very strong	47 Participants	33 Participants	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28: Preference for admin - fairly strong	12 Participants	6 Participants	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28: Preference for admin - not very strong	0 Participants	1 Participants	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28b: SC better long term option	12 Participants	—	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28b: IV better long term option	0 Participants	—	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28b: SC preferred administration	11 Participants	—	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28b: Preference for admin - very strong	11 Participants	—	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28b: Preference for admin - fairly strong	0 Participants	—	—	—	—	—
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Visit 28b: Preference for admin - not very strong	1 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline to week 13 for treatment period 1 and 2

The AE-QoL is a questionnaire on the quality of life of patients suffering from recurrent angioedema. It consists of 17 specific questions that are associated with work, physical activity, free time, social relations, and food. Each of the 17 questions has a five-point response scale ranging from 1 (Never) to 5 (Very Often). The AE-QoL consists of 4 dimensions (functioning=4 questions(qns) fatigue/mood=5 qns, fears/shame=6 qns, nutrition=2 qns) and a total score (all 17 questions).All scores were calculated by using the following formula: (Σ items - min Σ items / max Σ items - min Σ items) x 100. Σ items=sum of response by participant, min Σ items=minimum response possible, max Σ items=maximum response possible. Scores range from 0 to 100 , with higher scores indicating greater impairment. Absolute change calculated as visit score at week 13 minus score at baseline per period.

Outcome measures

Measure	Treatment C1 INH n=31 Participants Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm and in period 2 of the Placebo/Experimental arm).	Treatment Placebo n=28 Participants Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).	Placebo/Experimental Arm - Treatment Placebo n=29 Participants Participants randomized to the Placebo/Experimental arm received Placebo in treatment period 1.	Placebo/Experimental Arm - Treatment C1 INH n=25 Participants Participants randomized to the Placebo/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.	Experimental/Experimental Arm - Period 1 Treatment C1 INH n=15 Participants Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 1.	Experimental/Experimental Arm - Period 2 Treatment C1 INH n=15 Participants Participants randomized to the Experimental/Experimental arm received C1 Esterase Inhibitor (C1 INH) in treatment period 2.
Mean Change in Angioedema Quality of Life Questionnaire Scores From Baseline to Week 13 AE-QoL Total	-10.35 Mean change in AE-QoL scores Standard Deviation 17.75	4.77 Mean change in AE-QoL scores Standard Deviation 12.14	-6.86 Mean change in AE-QoL scores Standard Deviation 10.72	-12.10 Mean change in AE-QoL scores Standard Deviation 9.83	-11.65 Mean change in AE-QoL scores Standard Deviation 9.87	-0.52 Mean change in AE-QoL scores Standard Deviation 6.58
Mean Change in Angioedema Quality of Life Questionnaire Scores From Baseline to Week 13 Fatigue/Mood	-8.40 Mean change in AE-QoL scores Standard Deviation 21.94	2.44 Mean change in AE-QoL scores Standard Deviation 14.20	-9.11 Mean change in AE-QoL scores Standard Deviation 10.16	-10.10 Mean change in AE-QoL scores Standard Deviation 13.42	-8.40 Mean change in AE-QoL scores Standard Deviation 12.29	3.11 Mean change in AE-QoL scores Standard Deviation 9.33
Mean Change in Angioedema Quality of Life Questionnaire Scores From Baseline to Week 13 Nutrition	-11.00 Mean change in AE-QoL scores Standard Deviation 22.45	6.67 Mean change in AE-QoL scores Standard Deviation 19.70	-9.44 Mean change in AE-QoL scores Standard Deviation 25.55	-14.76 Mean change in AE-QoL scores Standard Deviation 17.50	-8.00 Mean change in AE-QoL scores Standard Deviation 16.19	-1.11 Mean change in AE-QoL scores Standard Deviation 7.82
Mean Change in Angioedema Quality of Life Questionnaire Scores From Baseline to Week 13 Functioning	-9.25 Mean change in AE-QoL scores Standard Deviation 21.29	6.11 Mean change in AE-QoL scores Standard Deviation 20.62	-10.56 Mean change in AE-QoL scores Standard Deviation 17.23	-23.33 Mean change in AE-QoL scores Standard Deviation 19.45	-20.50 Mean change in AE-QoL scores Standard Deviation 14.62	-2.78 Mean change in AE-QoL scores Standard Deviation 10.34
Mean Change in Angioedema Quality of Life Questionnaire Scores From Baseline to Week 13 Fear/Shame	-12.50 Mean change in AE-QoL scores Standard Deviation 21.46	5.19 Mean change in AE-QoL scores Standard Deviation 12.06	-1.67 Mean change in AE-QoL scores Standard Deviation 10.62	-5.40 Mean change in AE-QoL scores Standard Deviation 10.67	-9.67 Mean change in AE-QoL scores Standard Deviation 11.91	-1.85 Mean change in AE-QoL scores Standard Deviation 11.19

Adverse Events

Treatment C1 INH

Serious events: 2 serious events

Other events: 23 other events

Deaths: 0 deaths

Treatment Placebo

Serious events: 3 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Measure	Treatment C1 INH n=71 participants at risk Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm, in period 2 of the Placebo/Experimental arm and in period 1 and 2 of the Experimental/Experimental arm).	Treatment Placebo n=57 participants at risk Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).
Cardiac disorders Cardiac arrest	0.00% 0/71 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).	1.8% 1/57 • Number of events 1 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).
Congenital, familial and genetic disorders Hereditary angioedema	0.00% 0/71 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).	1.8% 1/57 • Number of events 1 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).
Hepatobiliary disorders Cholelithiasis	0.00% 0/71 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).	1.8% 1/57 • Number of events 1 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).
Infections and infestations Appendicitis	1.4% 1/71 • Number of events 1 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).	0.00% 0/57 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).
Infections and infestations Staphylococcal infection	1.4% 1/71 • Number of events 1 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).	0.00% 0/57 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).

Other adverse events

Measure	Treatment C1 INH n=71 participants at risk Participants who received C1 Esterase Inhibitor (C1 INH) treatment (in period 1 of the Experimental/Placebo arm, in period 2 of the Placebo/Experimental arm and in period 1 and 2 of the Experimental/Experimental arm).	Treatment Placebo n=57 participants at risk Participants who received Placebo treatment (in period 2 of the Experimental/Placebo arm and in period 1 of the Placebo/Experimental arm).
Infections and infestations Viral upper respiratory tract infection	15.5% 11/71 • Number of events 11 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).	5.3% 3/57 • Number of events 3 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).
Infections and infestations Upper respiratory tract infection	9.9% 7/71 • Number of events 7 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).	7.0% 4/57 • Number of events 4 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).
Injury, poisoning and procedural complications Contusion	0.00% 0/71 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).	5.3% 3/57 • Number of events 3 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).
Nervous system disorders Headache	8.5% 6/71 • Number of events 10 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).	10.5% 6/57 • Number of events 7 • Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
• Publication restrictions are in place

Restriction type: OTHER