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

• ClinicalTrials.gov Identifier: NCT01912456
• Recruitment Status: Completed
• First Posted: July 31, 2013
• Results First Posted: January 29, 2021
• Last Update Posted: January 29, 2021
• Sponsor: CSL Behring
• Information provided by (Responsible Party): CSL Behring

Tracking Information

• First Submitted Date: July 29, 2013
• First Posted Date: July 31, 2013
• Results First Submitted Date: December 11, 2020
• Results First Posted Date: January 29, 2021
• Last Update Posted Date: January 29, 2021
• Study Start Date: January 2014
• Actual Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 11, 2021)

The Time-normalized Number of Hereditary Angioedema Attacks [ Time Frame: During the treatment phase, up to 28 weeks. ]

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.

• Original Primary Outcome Measures (submitted: July 29, 2013): The time-normalized number of hereditary angioedema attacks [ Time Frame: During the treatment phase, up to 32 weeks. ]

Current Secondary Outcome Measures (submitted: January 11, 2021)

• Percentage of Subjects With a ≥ 50% Reduction in the Number of Hereditary Angioedema Attacks by CSL830 Treatment [ Time Frame: During the treatment phase, up to 28 weeks. ]
  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%.
• Time-Normalized Number of Uses of Rescue Medication [ Time Frame: During the treatment phase, up to 28 weeks. ]
  The time-normalized number of uses of rescue medication during treatment with C1-esterase inhibitor or placebo
• Percentage of Subjects With Adverse Events (AEs) Within 24 Hours of C1-esterase Inhibitor or Placebo Administration [ Time Frame: Within 24 hours of C1-esterase inhibitor or placebo administration. ]
• Percentage of Subjects With AEs or Other Specified Safety Events. [ Time Frame: During the treatment phase, up to 32 weeks. ]
  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.
• Percentage of Subjects Experiencing Solicited AEs (Injection Site Reactions) [ Time Frame: During the treatment phase, up to 32 weeks. ]
  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.
• Injections Resulting in Solicited AEs (Injection Site Reactions) [ Time Frame: During the treatment phase, up to 32 weeks. ]
  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.

Original Secondary Outcome Measures (submitted: July 29, 2013)

• Proportion of subjects with a 50% reduction in the number of hereditary angioedema attacks [ Time Frame: During the treatment phase, up to 32 weeks. ]
  The percentage of subjects with a 50% relative reduction in the time-normalized number of hereditary angioedema attacks during treatment with C1-esterase inhibitor compared with placebo
• Number of uses of rescue medication [ Time Frame: During the treatment phase, up to 32 weeks. ]
  The time-normalized number of uses of rescue medication during treatment with C1-esterase inhibitor or placebo
• Proportion of subjects with any adverse events [ Time Frame: During or within 24 hours of C1-esterase or placebo administration. ]
  The percentage of subjects with any adverse events that begin within 24 hours of administration of C1-esterase inhibitor or placebo

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate the Clinical Efficacy and Safety of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Hereditary Angioedema Types I and II

Intervention

• Biological: Low-volume C1-esterase inhibitor
• Biological: Higher-volume C1-esterase inhibitor
• Biological: Low-volume placebo
• Biological: Higher-volume placebo

Study Arms

• 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.
  Interventions:

  • 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.
  Interventions:

  • 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.
  Interventions:

  • 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.
  Interventions:

  • Biological: Higher-volume C1-esterase inhibitor
  • Biological: Low-volume placebo

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 12, 2016): 90
• Original Estimated Enrollment (submitted: July 29, 2013): 80
• Actual Study Completion Date: October 2015
• Actual Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Czechia, Hungary, Israel, Italy, Romania, Spain, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01912456
• Other Study ID Numbers: CSL830_3001; 2013-000916-10 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: CSL Behring
• Original Responsible Party: Same as current
• Current Study Sponsor: CSL Behring
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Global Clinical Program Director; CSL Behring

• PRS Account: CSL Behring
• Verification Date: January 2021