A Study to Evaluate the Clinical Efficacy and Safety of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema

A Double-blind, Randomized, Placebo-controlled, Cross-over Study to Evaluate the Clinical Efficacy and Safety of Subcutaneous Administration of Human Plasma-derived C1-esterase Inhibitor in the Prophylactic Treatment of Hereditary Angioedema

The aim of this study is to assess the efficacy of C1-esterase inhibitor in preventing hereditary angioedema attacks when it is administered under the skin of subjects with hereditary angioedema. The safety of C1-esterase inhibitor will also be assessed. Each subject will enter a run-in period of up to 8-weeks. Subjects who complete the run-in period and who are eligible will then enter the treatment phase which comprises two sequential treatment periods. In the treatment phase, subjects will be randomized to one of four arms consisting of treatment with low- or higher-volume C1-esterase inhibitor in one treatment period and treatment with low- or higher-volume placebo in the other treatment period. The study will measure the number of hereditary angioedema attacks that subjects experience while receiving each treatment.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema Types I and II
• Intervention / Treatment: Biological: Low-volume C1-esterase inhibitor; Biological: Higher-volume placebo; Biological: Higher-volume C1-esterase inhibitor; Biological: Low-volume placebo

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Campbelltown, New South Wales, Australia, 2560
      • Study Site
• Canada
  • Quebec, Canada, G1V 4M6
    • Study Site
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Study Site
    • Ottawa, Ontario, Canada, K1Y 4G2
      • Study Site
    • Toronto, Ontario, Canada, M4V 1R2
      • Study Site
• Czechia
  • Hradec Kralove, Czechia, 50005
    • Study Site
  • Plzen, Czechia, 30460
    • Study Site
• Hungary
  • Budapest, Hungary, 1125
    • Study Site
• Israel
  • Tel Aviv, Israel, 64239
    • Study Site
  • Tel Hashomer, Israel, 52621
    • Study Site
• Italy
  • Catania, Italy, 95123
    • Study Site
  • Palermo, Italy, 90146
    • Study Site
• Romania
  • Cluj Napoca, Romania, 400139
    • Study Site
  • Mures, Romania, 540103
    • Study Site
• Spain
  • Barcelona, Spain, 08035
    • Study Site
  • Madrid, Spain, 28007
    • Study Site
  • Madrid, Spain, 28046
    • Study Site
  • Valencia, Spain, 46026
    • Study Site
• United Kingdom
  • Brighton, United Kingdom, BN2 5BE
    • Study Site
  • London, United Kingdom, E1 2ES
    • Study Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Study Site
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Study Site
  • California
    • Bell Gardens, California, United States, 90201
      • Study Site
    • La Jolla, California, United States, 92093
      • Study Site
    • Orange, California, United States, 92868
      • Study Site
    • Walnut Creek, California, United States, 94598
      • Study Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Study Site
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Study Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Study Site
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0563
      • Study Site
    • Columbus, Ohio, United States, 43235
      • Study Site
    • Toledo, Ohio, United States, 43617
      • Study Site
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Study Site
  • Oregon
    • Lake Oswego, Oregon, United States, 97035
      • Study Site
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Study Site
  • Texas
    • Dallas, Texas, United States, 75231
      • Study Site
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Study Site
    • Virginia Beach, Virginia, United States, 23452
      • Study Site
  • Washington
    • Spokane, Washington, United States, 99204
      • Study Site

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

Inclusion Criteria:

Run-In Period Inclusion Criteria:

• Males or females aged 12 years or older.
• A clinical diagnosis of hereditary angioedema type I or II.
• Hereditary angioedema attacks over a consecutive 2-month period that required acute treatment, medical attention, or caused significant functional impairment.
• For subjects who have used oral therapy for prophylaxis against HAE attacks within 3 months of Screening: use of a stable regimen within 3 months of Screening, with no plans to change.

Eligibility Criteria for Entering Treatment Period 1:

• Laboratory confirmation of type I or type II hereditary angioedema, including C1-esterase inhibitor functional activity less than 50% AND C4 antigen level below the laboratory reference range.
• No clinically significant abnormalities as assessed using laboratory parameters.
• During participation in the run-in period, subjects must have experienced hereditary angioedema attacks that required acute treatment, required medical attention, or caused significant functional impairment.

Exclusion Criteria:

Run-In Period Exclusion Criteria:

• History of clinical significant arterial or venous thrombosis, or current history of a clinically significant prothrombotic risk.
• Incurable malignancies at screening.
• Any clinical condition that will interfere with the evaluation of C1-esterase inhibitor therapy.
• Clinically significant history of poor response to C1-esterase therapy for the management of hereditary angioedema.
• Receiving therapy prohibited by the protocol, including medications for hereditary angioedema prophylaxis.
• Female subjects who started taking or changed dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e., estrogen/progesterone-containing products) within 3 months prior to the screening visit.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Higher-volume placebo, then low-volume C1-esterase inhibitor; A higher-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks, then a low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.	Biological: Low-volume C1-esterase inhibitor; Biological: Higher-volume placebo
Experimental: Low-volume C1-esterase inhibitor, then higher-volume placebo; A low-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then a higher-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.	Biological: Low-volume C1-esterase inhibitor; Biological: Higher-volume placebo
Experimental: Low-volume placebo, then higher-volume C1-esterase inhibitor; A low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks then a higher-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks.	Biological: Higher-volume C1-esterase inhibitor; Biological: Low-volume placebo
Experimental: Higher-volume C1-esterase inhibitor, then low-volume placebo; A higher-volume dose of C1-esterase inhibitor will be administered subcutaneously twice a week for up to 16 weeks, then a low-volume dose of placebo will be administered subcutaneously twice a week for up to 16 weeks.	Biological: Higher-volume C1-esterase inhibitor; Biological: Low-volume placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Time-normalized Number of Hereditary Angioedema Attacks	The time normalized number of HAE attacks as reported by the investigator per subject was calculated as: The total number of HAE attacks per subject and per treatment period / length of stay of subject in treatment period (days), Where length of stay of subject in treatment period was calculated as: Date of last day of subject in treatment period - date of first day of Week 3 of subject in treatment period + 1.	During the treatment phase, up to 28 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects With a ≥ 50% Reduction in the Number of Hereditary Angioedema Attacks by CSL830 Treatment	The percentage reduction (%) in the time normalized number of HAE attacks was calculated as: 100 x [1 - (the time normalized number of HAE attacks when treated with CSL830) / (the time normalized number of HAE attacks when treated with placebo)]. A subject is classed as a responder if the percentage reduction is >= 50%.	During the treatment phase, up to 28 weeks.
Time-Normalized Number of Uses of Rescue Medication	The time-normalized number of uses of rescue medication during treatment with C1-esterase inhibitor or placebo	During the treatment phase, up to 28 weeks.
Percentage of Subjects With Adverse Events (AEs) Within 24 Hours of C1-esterase Inhibitor or Placebo Administration		Within 24 hours of C1-esterase inhibitor or placebo administration.
Percentage of Subjects With AEs or Other Specified Safety Events.	The percentage of subjects experiencing the following during treatment with CSL830 and placebo: unsolicited AEs, serious AEs, suspected adverse drug reactions, increased risk scores for deep vein thrombosis and pulmonary embolism, thromboembolic events, inhibitory anti C1 INH antibodies, or clinically significant abnormalities in laboratory assessments.	During the treatment phase, up to 32 weeks.
Percentage of Subjects Experiencing Solicited AEs (Injection Site Reactions)	The percentage of subjects experiencing solicited local AEs (discomfort [eg, pain, burning], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo.	During the treatment phase, up to 32 weeks.
Injections Resulting in Solicited AEs (Injection Site Reactions)	The rate/injection of injections of C1-esterase inhibitor or placebo that were followed by solicited local AEs (discomfort [eg, pain, burning], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo. Rate/Injection = Number of events/number of injections.	During the treatment phase, up to 32 weeks.

Collaborators and Investigators

• Sponsor: CSL Behring

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.
• Longhurst H, Cicardi M, Craig T, Bork K, Grattan C, Baker J, Li HH, Reshef A, Bonner J, Bernstein JA, Anderson J, Lumry WR, Farkas H, Katelaris CH, Sussman GL, Jacobs J, Riedl M, Manning ME, Hebert J, Keith PK, Kivity S, Neri S, Levy DS, Baeza ML, Nathan R, Schwartz LB, Caballero T, Yang W, Crisan I, Hernandez MD, Hussain I, Tarzi M, Ritchie B, Kralickova P, Guilarte M, Rehman SM, Banerji A, Gower RG, Bensen-Kennedy D, Edelman J, Feuersenger H, Lawo JP, Machnig T, Pawaskar D, Pragst I, Zuraw BL; COMPACT Investigators. Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor. N Engl J Med. 2017 Mar 23;376(12):1131-1140. doi: 10.1056/NEJMoa1613627.
• Li HH, Zuraw B, Longhurst HJ, Cicardi M, Bork K, Baker J, Lumry W, Bernstein J, Manning M, Levy D, Riedl MA, Feuersenger H, Prusty S, Pragst I, Machnig T, Craig T; COMPACT Investigators. Subcutaneous C1 inhibitor for prevention of attacks of hereditary angioedema: additional outcomes and subgroup analysis of a placebo-controlled randomized study. Allergy Asthma Clin Immunol. 2019 Aug 28;15:49. doi: 10.1186/s13223-019-0362-1. eCollection 2019.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: July 29, 2013
• First Submitted That Met QC Criteria: July 29, 2013
• First Posted (Estimate): July 31, 2013

Study Record Updates

• Last Update Posted (Actual): January 29, 2021
• Last Update Submitted That Met QC Criteria: January 11, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Hereditary Angioedema
• 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; Hereditary Angioedema Types I and II; 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: CSL830_3001; 2013-000916-10 (EudraCT Number)