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

• ClinicalTrials.gov Identifier: NCT01005888
• Recruitment Status: Completed
• First Posted: November 1, 2009
• Results First Posted: June 3, 2010
• Last Update Posted: June 11, 2021
• Sponsor: Shire
• Information provided by (Responsible Party): Takeda ( Shire )

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Hereditary Angioedema	Biological: C1 esterase inhibitor [human] (C1INH-nf); Drug: Placebo (saline)	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: March 14, 2005
• Actual Primary Completion Date: August 22, 2007
• Actual Study Completion Date: August 22, 2007

Arms and Interventions

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.	Biological: C1 esterase inhibitor [human] (C1INH-nf); Drug: Placebo (saline)
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.	Biological: C1 esterase inhibitor [human] (C1INH-nf); Drug: Placebo (saline)

Outcome Measures

Primary Outcome Measures :

1. Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period [ Time Frame: 12 weeks ]
   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).

Secondary Outcome Measures :

1. Number of Subject Withdrawals During Each Prophylactic Therapy Period [ Time Frame: 12 weeks ]
   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.
2. Average Severity of HAE Attacks During Each Prophylactic Therapy Period [ Time Frame: 12 weeks ]
   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.
3. Average Duration of HAE Attacks During Each Prophylactic Therapy Period [ Time Frame: 12 weeks ]
   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.
4. Number of Open-label C1INH-nf Infusions Required During Each Prophylactic Therapy Period [ Time Frame: 12 weeks ]
   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.
5. Antigenic C1 Inhibitor (C1INH) Serum Levels [ Time Frame: Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12 ]
   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.
6. Functional C1INH Serum Levels [ Time Frame: Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12 ]
   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).

Other Outcome Measures:

1. Total Number of Days of Swelling During Each Prophylactic Therapy Period [ Time Frame: 12 weeks ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 6 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Allergy and Immunology Associates

Scottsdale, Arizona, United States, 85251

United States, California

University of California, San Diego

San Diego, California, United States, 92093-0732

Allergy and Asthma Clinical Research, Inc

Walnut Creek, California, United States, 94598

United States, Georgia

Atlanta Allergy and Asthma Clinic

Suwanee, Georgia, United States, 30024

United States, Hawaii

Hawaii Pacific Health Research Institute

Honolulu, Hawaii, United States, 96826

United States, Indiana

Welborn Clinic Allergy and Immunology

Evansville, Indiana, United States, 47713

United States, Louisiana

Lake Charles Memorial Hospital

Lake Charles, Louisiana, United States, 70601

United States, Maryland

Institute for Asthma and Allergy

Wheaton, Maryland, United States, 20902

United States, Montana

Libby Clinic

Libby, Montana, United States, 59923

United States, New York

Mount Sinai School of Medicine

New York, New York, United States, 10029

United States, Ohio

Nationwide Childrens Hospital Clinical Research

Columbus, Ohio, United States, 43205

United States, Oklahoma

Allergy Clinic of Tulsa

Tulsa, Oklahoma, United States, 74133

United States, Oregon

Allergy Asthma and Dermatology Research Center

Lake Oswego, Oregon, United States, 97035

United States, Texas

AARA Research Center

Dallas, Texas, United States, 75231

Tyler County Hospital

Woodville, Texas, United States, 75979

United States, West Virginia

St. Joseph's Hospital/Cornerstone Healthcare

Parkersburg, West Virginia, United States, 26101

Sponsors and Collaborators

Shire

Investigators

• Study Director: Study Director; Takeda

More Information

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

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 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.

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.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01005888
• Other Study ID Numbers: LEVP2005-1/Part B
• First Posted: November 1, 2009
• Results First Posted: June 3, 2010
• Last Update Posted: June 11, 2021
• Last Verified: May 2021

Keywords provided by Takeda ( Shire ):

Hereditary angioedema; HAE; C1 esterase inhibitor (human); C1INH-nf

Additional relevant MeSH terms:

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