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

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).

Time frame: 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.

Time frame: 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.

Time frame: 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 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.

Time frame: Baseline to week 13 for treatment period 1 and 2

Angioedema attacks were normalized per month.

Time frame: 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.

Time frame: 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.

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.

Time frame: 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.

Time frame: Weeks 1 to 14 for treatment period 1 and 2

Anti-C1 INH antibodies were measured during study time.

Time frame: Weeks 1 to 14 for treatment period 1 and 2

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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).

Time frame: 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).

Time frame: 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). Participant wise data was reported for this outcome.

Time frame: 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).

Time frame: 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.

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

Time frame: 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

Time frame: 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. Participant wise data was reported for this outcome.

Time frame: 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

Time frame: 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.

tmax=time of maximum observed plasma concentration

Time frame: 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. Participant wise data was reported for this outcome.

Time frame: 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.

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).

Time frame: 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).

Time frame: 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).

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

Time frame: 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 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).

Time frame: 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.