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

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

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 Overview

• Status: Completed
• Conditions: Hereditary Angioedema (HAE)
• Intervention / Treatment: Drug: Placebo; Drug: C1 esterase inhibitor [human] liquid

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 325
      • McMaster University Medical Center
    • Ottawa, Ontario, Canada, K1Y 4G2
      • Ottawa Allergy Research Corporation
• Germany
  • Mörfelden-Walldorf, Germany, 64546
    • Hämophilie Zentrum Rhein Main GmbH
• Hungary
  • Budapest, Hungary, 1125
    • Semmelweis Egyetem
• Israel
  • Ramat-Gan, Israel, 52621
    • Chaim Sheba Medical Center
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
• Romania
  • Targu Mures, Romania, 540072
    • MediQuest Clinical Research Center
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe de Valencia
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Medical Research of Arizona
  • California
    • Santa Monica, California, United States, 90404
      • AIRE Medical of Los Angeles
    • Walnut Creek, California, United States, 94598
      • Bay Area Allergy
  • Colorado
    • Centennial, Colorado, United States, 80112
      • IMMUNOe Research Centers
    • Colorado Springs, Colorado, United States, 80907
      • Asthma and Allergy Associates PC
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Atlanta Allergy and Asthma Clinic
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Institute for Asthma and Allergy
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Washington University
  • New Jersey
    • Fair Lawn, New Jersey, United States, 07410
      • Allergy Asthma and Immunology
    • Iselin, New Jersey, United States, 08830
      • Allergy Treatment Center of New Jersey
  • North Carolina
    • Charlotte, North Carolina, United States, 28277
      • Clinical Research of Charlotte
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Bernstein Clinical Research Center Inc
    • Middleburg Heights, Ohio, United States, 44130
      • Clinical Research Solutions
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74133
      • Allergy Clinic of Tulsa
  • Texas
    • Dallas, Texas, United States, 75231
      • AARA Research Center
  • Washington
    • Spokane, Washington, United States, 99202
      • Premier Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

The maximum duration of participation is approximately 9 months. Patients will complete a screening period of up to 21 days. Following screening, eligible patients will be randomly assigned to 1 of 3 treatment sequences. Each patient will undergo 2 14-week treatment periods for a total of 28 weeks (Treatment Period 1 and Treatment Period 2). After completing the 2 treatment periods, patients will enter a 1-month follow-up period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Placebo; Placebo; Drug: C1 esterase inhibitor [human] liquid; C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days
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: Placebo; Placebo; Drug: C1 esterase inhibitor [human] liquid; C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days
Experimental: Experimental/ Experimental; Subjects will be randomized and receive C1 Esterase Inhibitor in both 1st as well as the 2nd treatment period	Drug: C1 esterase inhibitor [human] liquid; C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Weeks 1 to 14 for treatment period 1 and 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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).	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).	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).	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.	Weeks 1 to 14 for treatment period 1 and 2
Number of Attack-free Days	Attack free days were normalized per month.	Weeks 1 to 14 for treatment period 1 and 2
Number of Angioedema Attacks Requiring Acute Treatment	Angioedema attacks were normalized per month.	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.	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.	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.	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.	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).	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).	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).	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.	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	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	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	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.	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	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.	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.	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.	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.	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.	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.	Baseline to week 13 for treatment period 1 and 2

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K. Interventions for the long-term prevention of hereditary angioedema attacks. Cochrane Database Syst Rev. 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2.
• Lumry WR, Martinez-Saguer I, Yang WH, Bernstein JA, Jacobs J, Moldovan D, Riedl MA, Johnston DT, Li HH, Tang Y, Schranz J, Lu P, Vardi M, Farkas H; SAHARA study group. Fixed-Dose Subcutaneous C1-Inhibitor Liquid for Prophylactic Treatment of C1-INH-HAE: SAHARA Randomized Study. J Allergy Clin Immunol Pract. 2019 May-Jun;7(5):1610-1618.e4. doi: 10.1016/j.jaip.2019.01.021. Epub 2019 Jan 23.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): July 24, 2017
• Study Completion (Actual): July 24, 2017

Study Registration Dates

• First Submitted: October 20, 2015
• First Submitted That Met QC Criteria: October 21, 2015
• First Posted (Estimate): October 23, 2015

Study Record Updates

• Last Update Posted (Actual): June 8, 2021
• Last Update Submitted That Met QC Criteria: May 14, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Complement C1s
• Other Study ID Numbers: SHP616-300

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR