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

• ClinicalTrials.gov Identifier: NCT02584959
• Recruitment Status: Completed
• First Posted: October 23, 2015
• Results First Posted: November 28, 2018
• Last Update Posted: May 10, 2019
• Sponsor: Shire
• Information provided by (Responsible Party): Shire

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hereditary Angioedema (HAE)	Drug: C1 esterase inhibitor [human] liquid; Drug: Placebo	Phase 3

Study Design

• 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

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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).

Secondary Outcome Measures :

1. 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).
2. 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).
3. 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).
4. 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).
5. 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.

6. Number of Attack-free Days [ Time Frame: Weeks 1 to 14 for treatment period 1 and 2 ]
   Attack free days were normalized per month.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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).
13. 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).
14. 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).
15. 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.
16. 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
17. 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
18. 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
19. 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.

20. 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
21. 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.
22. 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.
23. 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.
24. 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.

25. 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.

26. 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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Arizona

Medical Research of Arizona

Scottsdale, Arizona, United States, 85251

United States, California

AIRE Medical of Los Angeles

Santa Monica, California, United States, 90404

Bay Area Allergy

Walnut Creek, California, United States, 94598

United States, Colorado

IMMUNOe Research Centers

Centennial, Colorado, United States, 80112

Asthma and Allergy Associates PC

Colorado Springs, Colorado, United States, 80907

United States, Georgia

Atlanta Allergy and Asthma Clinic

Marietta, Georgia, United States, 30060

United States, Maryland

Institute For Asthma and Allergy

Chevy Chase, Maryland, United States, 20815

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63141

United States, New Jersey

Allergy Asthma and Immunology

Fair Lawn, New Jersey, United States, 07410

Allergy Treatment Center of New Jersey

Iselin, New Jersey, United States, 08830

United States, North Carolina

Clinical Research of Charlotte

Charlotte, North Carolina, United States, 28277

United States, Ohio

Bernstein Clinical Research Center Inc

Cincinnati, Ohio, United States, 45231

Clinical Research Solutions

Middleburg Heights, Ohio, United States, 44130

United States, Oklahoma

Allergy Clinic of Tulsa

Tulsa, Oklahoma, United States, 74133

United States, Texas

AARA Research Center

Dallas, Texas, United States, 75231

United States, Washington

Premier Clinical Research

Spokane, Washington, United States, 99202

Canada, Ontario

McMaster University Medical Center

Hamilton, Ontario, Canada, L8N 325

Ottawa Allergy Research Corporation

Ottawa, Ontario, Canada, K1Y 4G2

Germany

Hämophilie Zentrum Rhein Main GmbH

Mörfelden-Walldorf, Germany, 64546

Hungary

Semmelweis Egyetem

Budapest, Hungary, 1125

Israel

Chaim Sheba Medical Center

Ramat-Gan, Israel, 52621

Tel Aviv Sourasky Medical Center

Tel Aviv, Israel, 64239

Romania

MediQuest Clinical Research Center

Targu Mures, Romania, 540072

Spain

Hospital Universitario Vall d'Hebron

Barcelona, Spain, 8035

Hospital Universitario La Paz

Madrid, Spain, 28046

Hospital Universitario Virgen del Rocio

Sevilla, Spain, 41013

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, Spain, 46026

Sponsors and Collaborators

Shire

Investigators

• Study Director: Shire Director; Shire

  Study Documents (Full-Text)

Documents provided by Shire:

Study Protocol: Protocol  [PDF] May 28, 2015

Study Protocol: Amendment1  [PDF] July 22, 2015

Study Protocol: Amendment2  [PDF] September 3, 2015

Study Protocol: Amendment3  [PDF] January 11, 2016

Study Protocol: Amendment4  [PDF] February 8, 2017

Statistical Analysis Plan  [PDF] August 17, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT02584959
• Other Study ID Numbers: SHP616-300
• First Posted: October 23, 2015
• Results First Posted: November 28, 2018
• Last Update Posted: May 10, 2019
• Last Verified: April 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided 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 in the Data Sharing section of the www.shiretrials.com website. 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://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

Additional relevant MeSH terms:

Angioedema; Angioedemas, Hereditary; Vascular Diseases; Cardiovascular Diseases; Urticaria; Skin Diseases, Vascular; Skin Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Genetic Diseases, Inborn; Complement C1s; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Immunologic Factors; Physiological Effects of Drugs; Complement Inactivating Agents; Immunosuppressive Agents