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

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

The study objective was to determine the safety and efficacy of C1INH-nf for the treatment 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

Randomized subjects treated for a qualifying attack were eligible to receive rescue dosing with 1,000 U of C1INH-nf if they did not achieve beginning of substantial relief of the defining symptom within 4 hours after initial treatment with blinded study drug, or if at any time the attack progressed to include airway compromise. A second 1,000 U rescue dose was permitted 60 minutes after the initial rescue dose, if necessary.

The study design also allowed for administration of open-label C1INH-nf for laryngeal angioedema attacks, which were non-randomizable events due to the presence of or potential for airway compromise (immediate 1,000 U dose of C1INH-nf, repeated after 60 minutes, if necessary). In addition, subjects were eligible to receive open-label C1INH-nf (1,000 U single dose) prior to emergency surgical (non-cosmetic) procedures.

A total of 83 subjects were enrolled in the study. Seventy-one (71) subjects experienced qualifying attacks and were randomized to blinded study drug (36 C1INH-nf, 35 placebo); only the 71 randomized subjects were analyzed for efficacy. An additional 12 subjects were never randomized but received open-label C1INH-nf for treatment of laryngeal angioedema and/or prior to emergency surgical procedures. Of the 35 subjects randomized to placebo, 23 also received C1INH-nf (eg, rescue, open-label). In total, 83 subjects received at least 1 dose of study drug and were analyzed for safety; 71 subjects were exposed to C1INH-nf (59 randomized, 12 open-label only) and 12 subjects were exposed only to placebo.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Hoover, Alabama, United States, 35216
      • Clinical Research Consultants, Inc
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Allergy and Immunology Associates
  • California
    • Los Angeles, California, United States, 90095
      • UCLA-David Geffen School of Medicine
    • San Diego, California, United States, 92093-0732
      • University of California, San Diego
    • Walnut Creek, California, United States, 94598
      • Allergy and Asthma Clinical Research, Inc
  • Florida
    • Fort Lauderdale, Florida, United States, 33334
      • Allergy and Asthma Center
    • Orlando, Florida, United States, 32806
      • Orlando Regional Healthcare
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Family Allergy and Asthma Center
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Welborn Clinic Allergy and Immunology
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospital and Clinic
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • The Baton Rouge Clinic, AMC
  • Maryland
    • Wheaton, Maryland, United States, 20902
      • Institute for Asthma and Allergy
  • Massachusetts
    • Falmouth, Massachusetts, United States, 02550
      • Allergy Asthma and Immunology
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • Michigan
    • Traverse City, Michigan, United States, 49684
      • Grand Traverse Allergy
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis University School of Medicine
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • Nevada Access to Research and Education Society
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • UMDNJ Asthma and Allergy Research Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • MeritCare Clinical Research
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Bernstein Clinical Research
    • Columbus, Ohio, United States, 43235
      • Optimed Research
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74133
      • Allergy Clinic of Tulsa
  • Oregon
    • Lake Oswego, Oregon, United States, 97035
      • Allergy Asthma and Dermatology Research Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State University
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Allergy Partners of the Upstate
  • Texas
    • Dallas, Texas, United States, 75231
      • AARA Research Center
    • Galveston, Texas, United States, 77555-1083
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78229
      • Allergy and Asthma Research Center
  • Virginia
    • Richmond, Virginia, United States, 23229
      • Virginia Adult and Pediatric Allergy and Asthma
  • Washington
    • Spokane, Washington, United States, 99204
      • Marycliff Allergy Specialists
    • Tacoma, Washington, United States, 98405
      • Puget Sound Allergy, Asthma and Immunology
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Allergy, Asthma and Pulmonary Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Documented HAE
• Normal C1q level

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: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: C1INH-nf; 1,000 Units (U) of C1INH-nf administered intravenously (IV). If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.	Biological: C1 esterase inhibitor [human] (C1INH-nf)
Placebo Comparator: Placebo; Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.	Drug: Placebo (saline)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Beginning of Substantial Relief of the Defining Symptom	Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug or until substantial relief of the defining symptom was achieved. Substantial relief was defined as 3 consecutive assessments of improvement of the defining symptom. Beginning of substantial relief was considered the first of the 3 consecutive assessments.	Within 4 hours after initial treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Beginning of Substantial Relief of the Defining Symptom	Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug or until substantial relief of the defining symptom was achieved. Substantial relief was defined as 3 consecutive assessments of improvement of the defining symptom. Beginning of substantial relief was considered the first of the 3 consecutive assessments.	Within 4 hours after initial treatment
Time to Complete Resolution of the HAE Attack	Randomized subjects were contacted 72-96 hours (3-4 days) after discharge from the study site to determine when complete resolution of the HAE attack occurred.	72 hours
Antigenic C1 Inhibitor (C1INH) Serum Levels	Change in antigenic C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug.	Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion
Functional C1INH Serum Levels	Percent change in functional C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (ie, functional C1INH/total detectable C1INH).	Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion
Complement C4 Serum Levels	Change in complement C4 serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug.	Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• 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.
• Grant JA, White MV, Li HH, Fitts D, Kalfus IN, Uknis ME, Lumry WR. Preprocedural administration of nanofiltered C1 esterase inhibitor to prevent hereditary angioedema attacks. Allergy Asthma Proc. 2012 Jul-Aug;33(4):348-53. doi: 10.2500/aap.2012.33.3585.

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2005
• Primary Completion (Actual): April 13, 2007
• Study Completion (Actual): April 13, 2007

Study Registration Dates

• First Submitted: February 7, 2006
• First Submitted That Met QC Criteria: February 7, 2006
• First Posted (Estimate): February 9, 2006

Study Record Updates

• Last Update Posted (Actual): June 11, 2021
• Last Update Submitted That Met QC Criteria: June 3, 2021
• Last Verified: June 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 A