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The study objective was to evaluate the safety and efficacy of repeat use of C1INH-nf for the treatment of acute HAE attacks.
A total of 113 subjects were enrolled in the study. One-hundred-one (101) subjects received C1INH-nf for the treatment of 1 or more HAE attacks and were analyzed for efficacy. The study design also allowed for short-term prophylaxis with C1INH-nf prior to emergency or non-cosmetic surgical or dental procedures, and an additional 12 subjects received C1INH-nf only for this purpose. All 113 subjects were exposed to C1INH-nf and analyzed for safety.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Open-label C1INH-nf | Experimental | 1,000 Units (U) of C1INH-nf administered intravenously. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| C1 esterase inhibitor [human] (C1INH-nf) | Biological |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Hereditary Angioedema (HAE) Attacks Treated With C1INH-nf | Duration of the study (2.5 years) | |
| Percent of HAE Attacks With Substantial Relief of the Defining Symptom | Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose or until substantial relief of the defining symptom was achieved. The conservative analysis defined substantial relief as 3 consecutive assessments of improvement of the defining symptom; any attack that did not have 3 consecutive documented reports of improvement was considered a treatment failure. In the less conservative analysis, attacks also were considered to have responded if clinical improvement of the defining symptom occurred but data were incomplete due to cessation of symptom assessments. | Within 4 hours after initial treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Beginning of Substantial Relief of the Defining Symptom | Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose 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. |
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Inclusion Criteria:
This study was open to all subjects who:
Completed participation in LEVP2005-1/A (NCT00289211) and were not participating in LEVP2005-1/B (NCT01005888), any time after the 3-day telephone follow-up
Completed participation in LEVP2005-1/B any time after the final prophylactic therapy in Part B
Were enrolled but not randomized in LEVP2005-1/A after Part A was closed
Were excluded from LEVP2005-1 for any of the following reasons:
Were not enrolled in LEVP2005-1 after enrollment in LEVP2005-1 was closed, under the following circumstances:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Takeda | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Allergy and Immunology Associates | Scottsdale | Arizona | 85251 | United States | ||
| Allergy and Asthma Clinic of Northwest Arkansas |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23484892 | Derived | Baker JW, Craig TJ, Riedl MA, Banerji A, Fitts D, Kalfus IN, Uknis ME. Nanofiltered C1 esterase inhibitor (human) for hereditary angioedema attacks in pregnant women. Allergy Asthma Proc. 2013 Mar-Apr;34(2):162-9. doi: 10.2500/aap.2013.34.3645. | |
| 23312695 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Open-label C1INH-nf | 1,000 Units (U) of C1 esterase inhibitor (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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Within 4 hours after initial treatment |
| Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | For attack number 1, the number of censored observations precluded estimation of the 95% confidence interval (CI) upper bound for median time to event (subjects who did not experience beginning of substantial relief of the defining symptom within 4 hours after initial treatment were included in the analysis as censored observations). Entry of 4.0 hours indicates that data were not estimable (NE); as non-numeric data are not supported by the 95% CI field, entry of the actual result (ie, NE or >4.0) was not possible. | Within 4 hours after initial treatment |
| Antigenic C1 Inhibitor (C1INH) Serum Levels | Change in antigenic C1INH serum levels from pre-infusion to 1 hour after the initial dose of study drug. | Pre-infusion to 1 hour post-infusion |
| Functional C1INH Serum Levels | Percent change in functional C1INH serum levels from pre-infusion to 1 hour after the initial dose of 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 hour post-infusion |
| Complement C4 Serum Levels | Change in complement C4 serum levels from pre-infusion to 1 hour after the initial dose of study drug. | Pre-infusion to 1 hour post-infusion |
| Bentonville |
| Arkansas |
| 72712 |
| United States |
| UCLA-David Geffen School of Medicine | Los Angeles | California | 90095 | United States |
| University of California, San Diego | San Diego | California | 92093-0732 | United States |
| Allergy and Asthma Clinical Research, Inc | Walnut Creek | California | 94598 | United States |
| Allergy and Asthma Center | Fort Lauderdale | Florida | 33334 | United States |
| Orlando Regional Healthcare | Orlando | Florida | 32806 | United States |
| Family Allergy and Asthma Center | Atlanta | Georgia | 30342 | United States |
| Welborn Clinic Allergy and Immunology | Evansville | Indiana | 47713 | United States |
| Institute for Asthma and Allergy | Wheaton | Maryland | 20902 | United States |
| University of Massachusetts Medical School | Worcester | Massachusetts | 01655 | United States |
| Grand Traverse Allergy | Traverse City | Michigan | 49684 | United States |
| MeritCare Clinical Research | Bemidji | Minnesota | 56601 | United States |
| Nevada Access to Research and Education Society | Las Vegas | Nevada | 89102 | United States |
| UMDNJ Asthma and Allergy Research Center | Newark | New Jersey | 07103 | United States |
| Winthrop University Hospital | Mineola | New York | 11501 | United States |
| Mount Sinai School of Medicine | New York | New York | 10029 | United States |
| Montefiore Medical Center | The Bronx | New York | 10461 | United States |
| MeritCare Clinical Research | Fargo | North Dakota | 58122 | United States |
| Allergy & Asthma Centre of Dayton | Centerville | Ohio | 45458 | United States |
| Allergy Clinic of Tulsa | Tulsa | Oklahoma | 74133 | United States |
| Allergy Asthma and Dermatology Research Center | Lake Oswego | Oregon | 97035 | United States |
| Penn State University | Hershey | Pennsylvania | 17033 | United States |
| Allergy Partners of the Upstate | Greenville | South Carolina | 29615 | United States |
| AARA Research Center | Dallas | Texas | 75231 | United States |
| University of Texas Medical Branch | Galveston | Texas | 77555-1083 | United States |
| Baylor College of Medicine | Houston | Texas | 77030 | United States |
| Allergy and Asthma Research Center | San Antonio | Texas | 78229 | United States |
| Marycliff Allergy Specialists | Spokane | Washington | 99204 | United States |
| Cornerstone Healthcare | Parkersburg | West Virginia | 26101 | United States |
| 22856635 | Derived | 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. |
| 22192966 | Derived | Riedl MA, Hurewitz DS, Levy R, Busse PJ, Fitts D, Kalfus I. Nanofiltered C1 esterase inhibitor (human) for the treatment of acute attacks of hereditary angioedema: an open-label trial. Ann Allergy Asthma Immunol. 2012 Jan;108(1):49-53. doi: 10.1016/j.anai.2011.10.017. Epub 2011 Nov 21. |
| 20818886 | Derived | 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. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Open-label C1INH-nf | 1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Hereditary Angioedema (HAE) Attacks Treated With C1INH-nf | Intent-to-treat Efficacy (ITT-E) Population (N=101; the number of subjects who received at least one dose of C1INH-nf for the treatment of an acute HAE attack). | Posted | Number | attacks | Duration of the study (2.5 years) |
|
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| Secondary | Time to Beginning of Substantial Relief of the Defining Symptom | Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose 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. | ITT-E Population. | Posted | Median | 95% Confidence Interval | hours | Within 4 hours after initial treatment |
|
| |||||||||||||||||||||||||||||||||
| Secondary | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | For attack number 1, the number of censored observations precluded estimation of the 95% confidence interval (CI) upper bound for median time to event (subjects who did not experience beginning of substantial relief of the defining symptom within 4 hours after initial treatment were included in the analysis as censored observations). Entry of 4.0 hours indicates that data were not estimable (NE); as non-numeric data are not supported by the 95% CI field, entry of the actual result (ie, NE or >4.0) was not possible. | ITT-E subjects with at least 10 HAE attacks during the study (N=15). | Posted | Median | 95% Confidence Interval | hours | Within 4 hours after initial treatment |
|
| |||||||||||||||||||||||||||||||||
| Secondary | Antigenic C1 Inhibitor (C1INH) Serum Levels | Change in antigenic C1INH serum levels from pre-infusion to 1 hour after the initial dose of study drug. | ITT-E subjects with data at both sampling time points (N=84). | Posted | Mean | Standard Deviation | mg/dL | Pre-infusion to 1 hour post-infusion |
|
| |||||||||||||||||||||||||||||||||
| Secondary | Functional C1INH Serum Levels | Percent change in functional C1INH serum levels from pre-infusion to 1 hour after the initial dose of study drug. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (ie, functional C1INH/total detectable C1INH). | ITT-E subjects with data at both sampling time points (N=82). | Posted | Mean | Standard Deviation | percent of functional C1INH | Pre-infusion to 1 hour post-infusion |
|
| |||||||||||||||||||||||||||||||||
| Secondary | Complement C4 Serum Levels | Change in complement C4 serum levels from pre-infusion to 1 hour after the initial dose of study drug. | ITT-E subjects with data at both sampling time points (N=74). | Posted | Mean | Standard Deviation | mg/dL | Pre-infusion to 1 hour post-infusion |
|
| |||||||||||||||||||||||||||||||||
| Primary | Percent of HAE Attacks With Substantial Relief of the Defining Symptom | Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose or until substantial relief of the defining symptom was achieved. The conservative analysis defined substantial relief as 3 consecutive assessments of improvement of the defining symptom; any attack that did not have 3 consecutive documented reports of improvement was considered a treatment failure. In the less conservative analysis, attacks also were considered to have responded if clinical improvement of the defining symptom occurred but data were incomplete due to cessation of symptom assessments. | ITT-E Population (N=101; the number of subjects who received at least one dose of C1INH-nf for the treatment of an acute HAE attack). | Posted | Number | percent of attacks | Within 4 hours after initial treatment |
|
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Presented are all treatment-emergent adverse reactions considered to be related to C1INH-nf.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Open-label C1INH-nf | 1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered. | 0 | 113 | 1 | 113 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infusion site pain | General disorders | MedDRA (9.0) |
| ||
| Rash | Skin and subcutaneous tissue disorders | MedDRA (9.0) |
|
Clinical Study Agreement. Most restrictive provision - PI will not publish results until after first of: multicenter publication is published or 24 months from study end. Thereafter, PI may publish his results. PI must provide copy of proposed publication to sponsor for pre-review. If sponsor requests, PI must delete sponsor confidential information before publication and/or delay publication for 90 days so sponsor can file for patents or take other action to protect its patent rights.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Shire | +1 866 842 5335 | ClinicalTransparency@shire.com |
| ID | Term |
|---|---|
| D054179 | Angioedemas, Hereditary |
| ID | Term |
|---|---|
| D000799 | Angioedema |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000081208 | Hereditary Complement Deficiency Diseases |
| D000081207 | Primary Immunodeficiency Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D014581 | Urticaria |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D007153 | Immunologic Deficiency Syndromes |
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| ID | Term |
|---|---|
| D050718 | Complement C1 Inhibitor Protein |
| ID | Term |
|---|---|
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D003174 | Complement C1 Inactivator Proteins |
| D015843 | Serpins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D003169 | Complement Inactivator Proteins |
| D003165 | Complement System Proteins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
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| Title | Denominators | Categories | ||||
|---|---|---|---|---|---|---|
| Pre-infusion |
| |||||
| Increase at 1 hour post-infusion |
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| Title | Denominators | Categories | ||||
|---|---|---|---|---|---|---|
| Pre-infusion |
| |||||
| Change at 1 hour post-infusion |
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