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
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ClinicalTrials.gov Identifier: NCT02584959 |
Recruitment Status :
Completed
First Posted : October 23, 2015
Results First Posted : November 28, 2018
Last Update Posted : June 8, 2021
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Hereditary Angioedema (HAE) | Drug: C1 esterase inhibitor [human] liquid Drug: Placebo | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 75 participants |
Allocation: | Randomized |
Intervention Model: | Crossover Assignment |
Masking: | Double (Participant, Investigator) |
Primary Purpose: | Prevention |
Official Title: | A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-sequence, Partial Crossover Study to Evaluate the Efficacy and Safety of Subcutaneous Administration of 2000 IU of C1 Esterase Inhibitor [Human] Liquid for Injection for the Prevention of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema |
Actual Study Start Date : | November 1, 2015 |
Actual Primary Completion Date : | July 24, 2017 |
Actual Study Completion Date : | July 24, 2017 |

Arm | Intervention/treatment |
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Experimental: Experimental/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.
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Drug: C1 esterase inhibitor [human] liquid
C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days Drug: Placebo Placebo |
Experimental: Placebo/Experimental
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.
|
Drug: C1 esterase inhibitor [human] liquid
C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days Drug: Placebo Placebo |
Experimental: Experimental/ Experimental
Subjects will be randomized and receive C1 Esterase Inhibitor in both 1st as well as the 2nd treatment period
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Drug: C1 esterase inhibitor [human] liquid
C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days |
- Time-Normalized Number of Attacks (NNA) for Participants During a Treatment Period [ Time Frame: 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).
- 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. [ Time Frame: 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).
- Time-Normalized Number of Attacks (NNA) for Participants During Each Treatment Period Excluding the First 2 Weeks. [ Time Frame: 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 Placebo Period Excluding the First 2 Weeks of Each Treatment Period. [ Time Frame: 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).
- 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. [ Time Frame: 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 [ Time Frame: 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.
- Number of Attack-free Days [ Time Frame: Weeks 1 to 14 for treatment period 1 and 2 ]Attack free days were normalized per month.
- Number of Angioedema Attacks Requiring Acute Treatment [ Time Frame: 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 [ Time Frame: 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) [ 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.
- Number of Participants With Injection Site Reactions [ Time Frame: 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.
- Number of Patients With Positive Anti-C1 INH Antibodies [ Time Frame: Weeks 1 to 14 for treatment period 1 and 2 ]Anti-C1 INH antibodies were measured during study time.
- PK Parameters: AUC (0-96) and AUC (0-t) for Functional C1 INH Binding Activity [ 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. ]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 C1 INH Antigen Concentrations [ 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. ]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) [ 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. ]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) [ 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. ]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 [ 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. ]Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
- PK Parameters: Cmax and Cmin for C1 INH Antigen Concentrations [ 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 ]Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
- PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment C1 INH) [ 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. ]Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
- PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment Placebo) [ 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. ]Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration. Participant wise data was reported for this outcome.
- PK Parameters: Tmax [ 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. ]tmax=time of maximum observed plasma concentration
- PK Parameters: Tmax for Complement C4 Concentrations (Placebo Group) [ 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. ]tmax=time of maximum observed plasma concentration. Participant wise data was reported for this outcome.
- Assess Disease Activity as Measured by the Angioedema Activity Score (AAS) Normalized Per Month [ Time Frame: 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: Overall Experience With the Syringe [ Time Frame: 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.
- Participant Experience With Self-administration: How Many Visits for Confidence With Self-administration [ Time Frame: 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 [ Time Frame: 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.
- Mean Change in Angioedema Quality of Life Questionnaire Scores From Baseline to Week 13 [ Time Frame: 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.

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Ages Eligible for Study: | 12 Years and older (Child, Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02584959

Study Director: | Study Director | Takeda |
Documents provided by Takeda ( Shire ):
Responsible Party: | Shire |
ClinicalTrials.gov Identifier: | NCT02584959 |
Other Study ID Numbers: |
SHP616-300 |
First Posted: | October 23, 2015 Key Record Dates |
Results First Posted: | November 28, 2018 |
Last Update Posted: | June 8, 2021 |
Last Verified: | May 2021 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement. |
Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) Clinical Study Report (CSR) |
Access Criteria: | IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement. |
URL: | https://vivli.org/ourmember/takeda/ |
Angioedema Angioedemas, Hereditary Vascular Diseases Cardiovascular Diseases Urticaria Skin Diseases, Vascular Skin Diseases Hypersensitivity, Immediate Hypersensitivity Immune System Diseases Hereditary Complement Deficiency Diseases |
Primary Immunodeficiency Diseases Genetic Diseases, Inborn Immunologic Deficiency Syndromes Complement C1s Complement C1 Inhibitor Protein Complement C1 Inactivator Proteins Immunologic Factors Physiological Effects of Drugs Complement Inactivating Agents Immunosuppressive Agents |