The purpose of this study is to assess the efficacy and safety of subcutaneous administration of a liquid formulation of C1 esterase inhibitor for the prevention of angioedema attacks in adolescent and adult subjects with hereditary angioedema.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
DOUBLE
Enrollment
75
C1 Esterase Inhibitor \[Human\] Liquid administered Subcutaneously as specified on specified days
Placebo
Time-Normalized Number of Attacks (NNA) for Participants During a Treatment Period
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
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.
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
Time-Normalized Number of Attacks (NNA) for Participants During Each Treatment Period Excluding the First 2 Weeks.
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
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.
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).
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Medical Research of Arizona
Scottsdale, Arizona, United States
AIRE Medical of Los Angeles
Santa Monica, California, United States
Bay Area Allergy
Walnut Creek, California, United States
IMMUNOe Research Centers
Centennial, Colorado, United States
Asthma and Allergy Associates PC
Colorado Springs, Colorado, United States
Atlanta Allergy and Asthma Clinic
Marietta, Georgia, United States
Institute For Asthma and Allergy
Chevy Chase, Maryland, United States
Washington University
St Louis, Missouri, United States
Allergy Asthma and Immunology
Fair Lawn, New Jersey, United States
Allergy Treatment Center of New Jersey
Iselin, New Jersey, United States
...and 17 more locations
Time frame: Weeks 3 to 14 for treatment period 1 and 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.
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
Cumulative Attack Severity
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
Number of Attack-free Days
Attack free days were normalized per month.
Time frame: Weeks 1 to 14 for treatment period 1 and 2
Number of Angioedema Attacks Requiring Acute Treatment
Angioedema attacks were normalized per month.
Time frame: Weeks 1 to 14 for treatment period 1 and 2
Response to Icatibant When Administered for an Acute Attack
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
Number of Patients With Adverse Events (AEs)
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
Number of Participants With Injection Site Reactions
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
Number of Patients With Positive Anti-C1 INH Antibodies
Anti-C1 INH antibodies were measured during study time.
Time frame: Weeks 1 to 14 for treatment period 1 and 2
PK Parameters: AUC (0-96) and AUC (0-t) for Functional C1 INH Binding Activity
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.
PK Parameters: AUC (0-96) and AUC (0-t) for C1 INH Antigen Concentrations
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.
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treamtment C1 INH)
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.
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treatment Placebo)
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.
PK Parameters: Cmax and Cmin for Functional C1 INH Binding Activity
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.
PK Parameters: Cmax and Cmin for C1 INH Antigen Concentrations
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
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment C1 INH)
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.
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment Placebo)
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.
PK Parameters: Tmax
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.
PK Parameters: Tmax for Complement C4 Concentrations (Placebo Group)
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.
Assess Disease Activity as Measured by the Angioedema Activity Score (AAS) Normalized Per Month
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
Participant Experience With Self-administration: Overall Experience With the Syringe
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
Participant Experience With Self-administration: How Many Visits for Confidence With Self-administration
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
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration
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
Mean Change in Angioedema Quality of Life Questionnaire Scores From Baseline to Week 13
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