C1 Esterase Inhibitor (C1INH-nf) for the Prevention of Acute Hereditary Angioedema (HAE) Attacks

LEVP2005-1/Part B: A Double-blind, Placebo-Controlled, Clinical Study to Investigate the Efficacy and Safety of Purified C1 Esterase Inhibitor (Human) as Prophylactic Treatment to Prevent HAE Attacks

The study objective was to determine the safety and efficacy of C1INH-nf for the prevention of acute HAE attacks.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Drug: Placebo (saline); Biological: C1 esterase inhibitor [human] (C1INH-nf)

Detailed Description

Subjects were given diary cards and instructed to document all HAE attacks on a daily basis. Subjects evaluated their symptoms over the previous 24 hours, noting the severity and duration of swelling at each of 5 locations (abdominal, genitourinary, facial, respiratory [including laryngeal], and/or extremity).

The study design also allowed for administration of open-label C1INH-nf (1,000 U of C1INH-nf administered IV [repeated after 60 minutes, if necessary] for treatment of laryngeal angioedema or if deemed necessary by the investigator; 1,000 U of C1INH-nf administered IV [single dose] prior to emergency surgical procedures).

A total of 26 subjects were enrolled in the study. One subject received open-label C1INH-nf but withdrew prior to randomization. Another subject was randomized but withdrew prior to receiving study drug. Twenty-four (24) subjects were randomized and treated with blinded study drug. In total, 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 subjects were exposed to C1INH-nf and 23 subjects were exposed to placebo.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Allergy and Immunology Associates
  • California
    • San Diego, California, United States, 92093-0732
      • University of California, San Diego
    • Walnut Creek, California, United States, 94598
      • Allergy and Asthma Clinical Research, Inc
  • Georgia
    • Suwanee, Georgia, United States, 30024
      • Atlanta Allergy and Asthma Clinic
  • Hawaii
    • Honolulu, Hawaii, United States, 96826
      • Hawaii Pacific Health Research Institute
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Welborn Clinic Allergy and Immunology
  • Louisiana
    • Lake Charles, Louisiana, United States, 70601
      • Lake Charles Memorial Hospital
  • Maryland
    • Wheaton, Maryland, United States, 20902
      • Institute for Asthma and Allergy
  • Montana
    • Libby, Montana, United States, 59923
      • Libby Clinic
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Childrens Hospital Clinical Research
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74133
      • Allergy Clinic of Tulsa
  • Oregon
    • Lake Oswego, Oregon, United States, 97035
      • Allergy Asthma and Dermatology Research Center
  • Texas
    • Dallas, Texas, United States, 75231
      • AARA Research Center
    • Woodville, Texas, United States, 75979
      • Tyler County Hospital
  • West Virginia
    • Parkersburg, West Virginia, United States, 26101
      • St. Joseph's Hospital/Cornerstone Healthcare

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Documented HAE
• Normal C1q level
• Relatively frequent angioedema attacks (at least 2 per month on average)

Exclusion Criteria:

• Low C1q level
• B-cell malignancy
• Presence of anti-C1INH autoantibody
• History of allergic reaction to C1INH or other blood products
• Narcotic addiction
• Current participation in any other investigational drug study or within the past 30 days
• Participation in a C1 esterase inhibitor trial, or received blood or a blood product in the past 90 days
• Pregnancy or lactation
• Any clinically significant medical condition, such as renal failure, that in the opinion of the investigator would interfere with the subject's ability to participate in the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: C1INH-nf First, then Placebo; 1,000 Units (U) of C1INH-nf administered intravenously (IV) every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by matching placebo (saline) administered IV every 3 to 4 days for 12 weeks.	Drug: Placebo (saline); Biological: C1 esterase inhibitor [human] (C1INH-nf)
Experimental: Placebo First, then C1INH-nf; Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by 1,000 U of C1INH-nf administered IV every 3 to 4 days for 12 weeks.	Drug: Placebo (saline); Biological: C1 esterase inhibitor [human] (C1INH-nf)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period	An HAE attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day. Analyses include observed attack counts and normalized attack counts (i.e., the number of attacks observed during each therapy period, normalized for the number of days the subject participated in that period).	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subject Withdrawals During Each Prophylactic Therapy Period	At the end of each therapy period, each subject was assigned a yes/no drop-out status. A drop-out was defined as a subject who did not have a Week 12 visit record.	12 weeks
Average Severity of HAE Attacks During Each Prophylactic Therapy Period	All attacks in each therapy period were assigned a value of 1 (mild), 2 (moderate), or 3 (severe). Attack severity was considered the highest value assigned by the subject to any swelling location during the attack. Average severity was set to 0 if there was no attack in a period.	12 weeks
Average Duration of HAE Attacks During Each Prophylactic Therapy Period	The duration of an attack was measured from the first report of swelling at any one of the five locations (abdominal, genitourinary, facial, respiratory [including laryngeal], or extremity) until the first subsequent report of "no swelling" at all five locations.	12 weeks
Number of Open-label C1INH-nf Infusions Required During Each Prophylactic Therapy Period	The study design allowed for subjects to be treated with open-label C1INH-nf for laryngeal angioedema, if deemed necessary by the investigator, or prior to emergency surgical procedures.	12 weeks
Antigenic C1 Inhibitor (C1INH) Serum Levels	Change in antigenic C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits.	Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12
Functional C1INH Serum Levels	Percent change in functional C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (i.e., functional C1INH/total detectable C1INH).	Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of Days of Swelling During Each Prophylactic Therapy Period	A day of swelling was defined as a day that a subject reported swelling at any of the five locations (abdominal, genitourinary, facial, respiratory [including laryngeal], or extremity).	12 weeks

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 W, Manning ME, Hurewitz DS, Davis-Lorton M, Fitts D, Kalfus IN, Uknis ME. Nanofiltered C1-esterase inhibitor for the acute management and prevention of hereditary angioedema attacks due to C1-inhibitor deficiency in children. J Pediatr. 2013 May;162(5):1017-22.e1-2. doi: 10.1016/j.jpeds.2012.11.030. Epub 2013 Jan 11.
• Zuraw BL, Busse PJ, White M, Jacobs J, Lumry W, Baker J, Craig T, Grant JA, Hurewitz D, Bielory L, Cartwright WE, Koleilat M, Ryan W, Schaefer O, Manning M, Patel P, Bernstein JA, Friedman RA, Wilkinson R, Tanner D, Kohler G, Gunther G, Levy R, McClellan J, Redhead J, Guss D, Heyman E, Blumenstein BA, Kalfus I, Frank MM. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010 Aug 5;363(6):513-22. doi: 10.1056/NEJMoa0805538.
• Lumry WR, Miller DP, Newcomer S, Fitts D, Dayno J. Quality of life in patients with hereditary angioedema receiving therapy for routine prevention of attacks. Allergy Asthma Proc. 2014 Sep-Oct;35(5):371-6. doi: 10.2500/aap.2014.35.3783.

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2005
• Primary Completion (Actual): August 22, 2007
• Study Completion (Actual): August 22, 2007

Study Registration Dates

• First Submitted: October 29, 2009
• First Submitted That Met QC Criteria: October 30, 2009
• First Posted (Estimate): November 1, 2009

Study Record Updates

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

More Information

Terms related to this study

• Keywords: HAE; Hereditary angioedema; C1 esterase inhibitor (human); C1INH-nf
• 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: LEVP2005-1/Part B