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The study objective was to determine the safety and efficacy of C1INH-nf for the treatment of acute HAE attacks.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| C1INH-nf | Experimental | 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. |
|
| Placebo | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| C1 esterase inhibitor [human] (C1INH-nf) | Biological |
| ||
| Placebo (saline) |
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Takeda | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Research Consultants, Inc | Hoover | Alabama | 35216 | United States | ||
| Allergy and Immunology Associates |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 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. | |
| 22856635 |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Placebo |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Drug |
|
| 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 |
| Scottsdale |
| Arizona |
| 85251 |
| 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 |
| University of Iowa Hospital and Clinic | Iowa City | Iowa | 52242 | United States |
| The Baton Rouge Clinic, AMC | Baton Rouge | Louisiana | 70808 | United States |
| Institute for Asthma and Allergy | Wheaton | Maryland | 20902 | United States |
| Allergy Asthma and Immunology | Falmouth | Massachusetts | 02550 | United States |
| University of Massachusetts Medical School | Worcester | Massachusetts | 01655 | United States |
| Grand Traverse Allergy | Traverse City | Michigan | 49684 | United States |
| St. Louis University School of Medicine | St Louis | Missouri | 63110 | 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 |
| Duke University Medical Center | Durham | North Carolina | 27710 | United States |
| MeritCare Clinical Research | Fargo | North Dakota | 58122 | United States |
| Bernstein Clinical Research | Cincinnati | Ohio | 45231 | United States |
| Optimed Research | Columbus | Ohio | 43235 | 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 |
| Virginia Adult and Pediatric Allergy and Asthma | Richmond | Virginia | 23229 | United States |
| Marycliff Allergy Specialists | Spokane | Washington | 99204 | United States |
| Puget Sound Allergy, Asthma and Immunology | Tacoma | Washington | 98405 | United States |
| Allergy, Asthma and Pulmonary Clinical Research | Madison | Wisconsin | 53792 | United States |
| 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. |
| 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. |
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.
| FG002 | Open-label C1INH-nf Only | Twelve subjects were never randomized but received open-label C1INH-nf for treatment of laryngeal angioedema and/or prior to emergency surgical procedures. These subjects were analyzed for safety only. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | Open-label C1INH-nf Only | Twelve subjects were never randomized but received open-label C1INH-nf for treatment of laryngeal angioedema and/or prior to emergency surgical procedures. These subjects were analyzed for safety only. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| 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 | 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. | Intent-to-treat (ITT) Population (all randomized subjects). Since less than 50% of subjects in the placebo group achieved the endpoint, median time to event was not estimable (NE). Further, the number of censored events in the C1INH-nf and placebo groups precluded estimation of the 95% confidence interval (CI) upper bound for median time to event. | Posted | Median | 95% Confidence Interval | hours | Within 4 hours after initial treatment |
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| Secondary | 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. | ITT-Efficacy (ITT-E) Population (N=68; 3 of the 71 randomized [ie, ITT] subjects were excluded from the ITT-E Population, as it was later determined that they did not experience a definitive hereditary angioedema [HAE] attack). | Posted | Number | participants | Within 4 hours after initial treatment |
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| Secondary | 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. | ITT Population. | Posted | Median | 95% Confidence Interval | hours | 72 hours |
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| Secondary | 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. | ITT-E subjects (N=68) with data available. | Posted | Mean | Standard Deviation | mg/dL | Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion |
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| Secondary | 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). | ITT-E subjects (N=68) with data available. | Posted | Mean | Standard Deviation | percent of functional C1INH | Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion |
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| Secondary | 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. | ITT-E subjects (N=68) with data available. | Posted | Mean | Standard Deviation | mg/dL | Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion |
|
|
3 months. As the study design allowed for all subjects (even those randomized to placebo) to receive C1INH-nf, safety data are presented by actual treatment received (C1INH-nf 71, placebo 12), not randomized treatment group (see Detailed Description).
Presented are all treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse events reported in this study.
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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 | C1INH-nf | 0 | 71 | 2 | 71 | |||
| EG001 | Placebo | 0 | 12 | 1 | 12 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dermatitis contact | Skin and subcutaneous tissue disorders | MedDRA (9.0) |
| ||
| Injection site rash | General disorders | MedDRA (9.0) |
| ||
| Tetany | Metabolism and nutrition disorders | MedDRA (9.0) |
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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 |
| D012965 | Sodium Chloride |
| 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 |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
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