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

Hereditary Angioedema (HAE) Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02584959
• Other study ID #: SHP616-300
• Status: Completed
• Phase: Phase 3
• Start date: November 1, 2015
• Est. completion date: July 24, 2017

Study information

• Verified date: May 2021
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 75
• Est. completion date: July 24, 2017
• Est. primary completion date: July 24, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Angioedema
• Hereditary Angioedema (HAE)

Intervention

Drug:
• C1 esterase inhibitor [human] liquid
C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days
• Placebo
Placebo

Locations

Country	Name	City	State
Canada	McMaster University Medical Center	Hamilton	Ontario
Canada	Ottawa Allergy Research Corporation	Ottawa	Ontario
Germany	Hämophilie Zentrum Rhein Main GmbH	Mörfelden-Walldorf
Hungary	Semmelweis Egyetem	Budapest
Israel	Chaim Sheba Medical Center	Ramat-Gan
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Romania	MediQuest Clinical Research Center	Targu Mures
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
United States	IMMUNOe Research Centers	Centennial	Colorado
United States	Clinical Research of Charlotte	Charlotte	North Carolina
United States	Institute For Asthma and Allergy	Chevy Chase	Maryland
United States	Bernstein Clinical Research Center Inc	Cincinnati	Ohio
United States	Asthma and Allergy Associates PC	Colorado Springs	Colorado
United States	AARA Research Center	Dallas	Texas
United States	Allergy Asthma and Immunology	Fair Lawn	New Jersey
United States	Allergy Treatment Center of New Jersey	Iselin	New Jersey
United States	Atlanta Allergy and Asthma Clinic	Marietta	Georgia
United States	Clinical Research Solutions	Middleburg Heights	Ohio
United States	Washington University	Saint Louis	Missouri
United States	AIRE Medical of Los Angeles	Santa Monica	California
United States	Medical Research of Arizona	Scottsdale	Arizona
United States	Premier Clinical Research	Spokane	Washington
United States	Allergy Clinic of Tulsa	Tulsa	Oklahoma
United States	Bay Area Allergy	Walnut Creek	California

Sponsors (1)

Lead Sponsor	Collaborator
Shire

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Hungary,  Israel,  Romania,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Number of Attack-free Days	Attack free days were normalized per month.	Weeks 1 to 14 for treatment period 1 and 2
Secondary	Number of Angioedema Attacks Requiring Acute Treatment	Angioedema attacks were normalized per month.	Weeks 1 to 14 for treatment period 1 and 2
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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: (S items - min S items / max S items - min S items) x 100. S items=sum of response by participant, min S items=minimum response possible, max S 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