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
- Conditions
- Hereditary Angioedema (HAE)
- Interventions
- Drug: C1 esterase inhibitor [human] liquidDrug: Placebo
- Registration Number
- NCT02584959
- Lead Sponsor
- Shire
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 75
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Experimental/Placebo C1 esterase inhibitor [human] liquid Subjects will be randomized to receive C1 Esterase Inhibitor in the 1st Treatment period and then switch to Placebo in the 2nd treatment period. Experimental/Placebo Placebo 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 C1 esterase inhibitor [human] liquid 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. Placebo/Experimental Placebo 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 C1 esterase inhibitor [human] liquid Subjects will be randomized and receive C1 Esterase Inhibitor in both 1st as well as the 2nd treatment period
- Primary Outcome Measures
Name Time Method Time-Normalized Number of Attacks (NNA) for Participants During a Treatment Period Weeks 1 to 14 for treatment period 1 and 2 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).
- Secondary Outcome Measures
Name Time Method Time-Normalized Number of Attacks (NNA) for Participants During Each Treatment Period Excluding the First 2 Weeks. Weeks 3 to 14 for treatment period 1 and 2 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).
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. Weeks 1 to 14 for treatment period 1 and 2 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).
Cumulative Attack Severity Weeks 1 to 14 for treatment period 1 and 2 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.
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. Weeks 1 to 14 for treatment period 1 and 2 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).
Number of Patients With Positive Anti-C1 INH Antibodies Weeks 1 to 14 for treatment period 1 and 2 Anti-C1 INH antibodies were measured during study time.
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. Weeks 3 to 14 for treatment period 1 and 2 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).
Number of Attack-free Days Weeks 1 to 14 for treatment period 1 and 2 Attack free days were normalized per month.
Number of Angioedema Attacks Requiring Acute Treatment Weeks 1 to 14 for treatment period 1 and 2 Angioedema attacks were normalized per month.
Response to Icatibant When Administered for an Acute Attack Weeks 1 to 14 for treatment period 1 and 2 The number of Acute Hereditary Angioedema Attacks that required Icatibant as acute therapy is presented by the number of Icatibant injections.
Number of Patients With Adverse Events (AEs) 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.
Number of Participants With Injection Site Reactions 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.
PK Parameters: AUC (0-96) and AUC (0-t) for Functional C1 INH Binding Activity 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. 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).
Assess Disease Activity as Measured by the Angioedema Activity Score (AAS) Normalized Per Month Weeks 1 to 14 for treatment period 1 and 2 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.
Participant Experience With Self-administration: How Many Visits for Confidence With Self-administration Week 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.
Participant Experience With Self-administration: Better Long-term Option and Preferred Administration Week 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.
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment C1 INH) 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. Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
Mean Change in Angioedema Quality of Life Questionnaire Scores From Baseline to Week 13 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.
PK Parameters: AUC (0-96) and AUC (0-t) for C1 INH Antigen Concentrations 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. 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).
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treamtment C1 INH) 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. 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).
PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treatment Placebo) 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. 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.
PK Parameters: Cmax and Cmin for Functional C1 INH Binding Activity 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. Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
PK Parameters: Cmax and Cmin for C1 INH Antigen Concentrations 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 Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment Placebo) 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. Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration. Participant wise data was reported for this outcome.
PK Parameters: Tmax 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. tmax=time of maximum observed plasma concentration
PK Parameters: Tmax for Complement C4 Concentrations (Placebo Group) 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. tmax=time of maximum observed plasma concentration. Participant wise data was reported for this outcome.
Participant Experience With Self-administration: Overall Experience With the Syringe Week 14 for treatment period 1 and 2 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.
Trial Locations
- Locations (27)
AIRE Medical of Los Angeles
🇺🇸Santa Monica, California, United States
Atlanta Allergy and Asthma Clinic
🇺🇸Marietta, Georgia, United States
Bay Area Allergy
🇺🇸Walnut Creek, California, United States
Asthma and Allergy Associates PC
🇺🇸Colorado Springs, Colorado, United States
Institute For Asthma and Allergy
🇺🇸Chevy Chase, Maryland, United States
Washington University
🇺🇸Saint Louis, Missouri, United States
Allergy Asthma and Immunology
🇺🇸Fair Lawn, New Jersey, United States
Clinical Research of Charlotte
🇺🇸Charlotte, North Carolina, United States
Bernstein Clinical Research Center Inc
🇺🇸Cincinnati, Ohio, United States
Premier Clinical Research
🇺🇸Spokane, Washington, United States
AARA Research Center
🇺🇸Dallas, Texas, United States
Allergy Clinic of Tulsa
🇺🇸Tulsa, Oklahoma, United States
McMaster University Medical Center
🇨🇦Hamilton, Ontario, Canada
Hämophilie Zentrum Rhein Main GmbH
🇩🇪Mörfelden-Walldorf, Germany
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitari i Politecnic La Fe de Valencia
🇪🇸Valencia, Spain
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Spain
Medical Research of Arizona
🇺🇸Scottsdale, Arizona, United States
Clinical Research Solutions
🇺🇸Middleburg Heights, Ohio, United States
Ottawa Allergy Research Corporation
🇨🇦Ottawa, Ontario, Canada
MediQuest Clinical Research Center
🇷🇴Targu Mures, Romania
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Chaim Sheba Medical Center
🇮🇱Ramat-Gan, Israel
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
IMMUNOe Research Centers
🇺🇸Centennial, Colorado, United States
Allergy Treatment Center of New Jersey
🇺🇸Iselin, New Jersey, United States
Semmelweis Egyetem
🇭🇺Budapest, Hungary