Efficacy of Human C1 esterase Inhibitor concentrate compared with Placebo in Acute Hereditary Angioedema Attacks

Penn State University College of Medicine, Hershey, Pa., USA.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 09/2009; 124(4):801-8. DOI: 10.1016/j.jaci.2009.07.017
Source: PubMed


Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder.
To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema.
This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours.
Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus.
C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

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Available from: Heinz-Otto Keinecke, Sep 09, 2015
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    • "This range in dosing can be explained by to the long duration of the study (1997-2013). Prior to the IMPACT-1 trial in 2009, the dose of 10 U/kg was used as standard; however after the IMPACT-1 trial found that 20 U/kg was superior to 10 U/kg [5], this dose was utilized instead. "
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    ABSTRACT: Hereditary Angioedema (HAE) is a rare autosomal dominant condition characterized by episodic angioedema, which may be triggered by invasive procedures and surgery. C1 inhibitor (C1 INH) was approved in the United States and Canada in 2009 and 2010, respectively, for the treatment of acute attacks. Most recently in April 2013, it was approved in Europe for short-term prophylaxis (STP), prior to medical, dental, or surgical procedures, to prevent HAE attacks in both children and adults. Currently, C1 INH is not approved in Canada or the United States for STP of HAE attacks. Our objective was to demonstrate the effectiveness of C1 INH as a short-term prophylactic treatment for patients with Type I HAE undergoing invasive surgical procedures. A retrospective chart review between 1997-2013 was performed at one Canadian Tertiary Care Allergy and Asthma Clinic affiliated with The Ottawa Hospital, in Ottawa, Canada. The standard dose of C1 INH for STP was 10 or 20 U/kg. In all 24 procedures, there were no post-procedure HAE attacks after short-term prophylactic administration of C1 INH. In this retrospective chart review at one tertiary care Allergy and Clinical Immunology Clinic, short-term prophylactic use of C1 INH was found to be effective at preventing post-procedure HAE attacks, in patients diagnosed with Type I HAE.
    Full-text · Article · Apr 2014 · Allergy Asthma and Clinical Immunology
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    • "Therapeutic administration of C1-inh is clinically applied in the context of hereditary angioedema (HAE), which is hallmarked by heterozygous C1-inh deficiency (Donaldson & Evans, 1963). Randomized controlled trials in patients demonstrated that C1-inh administration effectively decreased the severity of HAE-episodes, without having serious side-effects (Kunschak et al., 1998; Craig et al., 2009). "
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    ABSTRACT: Abstract Context: C1-esterase inhibitor (C1-inh) therapy is currently administered to patients with C1-inh deficiency through intravenous injections. The possibility of subcutaneous administration is currently being explored since this would alleviate need for hospitalization and increase mobility and well-being of patients. Recently, it was observed in pigs that C1-inh indeed can effectively be applied by subcutaneous injection. For studies on the effectiveness of C1-inh therapy for other indications than acquired and hereditary angioedema, rats are commonly used as model animal. For rats, however, subcutaneous C1-inh administration has never been investigated. Objective: To evaluate the efficacy of subcutaneous C1-inh administration in rats. Materials and methods: Three boli of 100 U/kg human plasma-derived C1-inh were administered to Wistar rats on three consecutive days through subcutaneous injection or intravenous injection. Blood samples were collected from the tail veins 3, 4.5 or 6 h after C1-inh administration for measurement of C1-inh plasma levels. Antigen and activity levels of C1-inh of each plasma sample were determined by means of a specific ELISA. Results: For both C1-inh antigen and C1-inh activity, 21- to 119-fold higher plasma levels were measured after intravenous administration compared with subcutaneous administration. Subcutaneous administration also resulted in C1-inh plasma levels that were less stable and with decreased relative activity. Conclusion: These combined results indicate that in rats, subcutaneous injections in the present formulation are not effective as alternative administration route for C1-inh.
    Full-text · Article · Nov 2013 · Drug Delivery
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    • "An evidence-based consensus guideline was reframed by 58 HAE expert physicians named as HAWK (Hereditary Angioedema International Working Group) in an International conference held in Gargnano del Garda, Italy, in September 2010 and published in February 2012.23 The recommendations, based on high-quality double-blind, randomized, placebo-controlled trials for the treatment of acute attacks “on demand” in all patients (even if asymptomatic) with HAE owing to C1-INH deficiency, indicated that plasma-derived (Berinert®; CSL Behring, King of Prussia, PA, USA; Cinryze®; ViroPharma Incorporated, Exton, PA, USA; Cetor®; San Quin, Amsterdam, Netherlands) and recombinant C1-INH concentrates (Rhucin®in USA, Santarus, Inc, San Diego, CA, USA, /Ruconest™ in Europe; Pharming NV, Leiden, Netherlands), Kallikrein inhibitor ecallantide (Kalbitor®; Dyax Corporation, Cambridge, MA, USA), or bradykinin B2 receptor antagonist icatibant (Firazyr®; Shire Human Genetic Therapies AB, Lund, Sweden) are appropriate and efficacious.24–28,41 Moreover, it is highly desirable that one of these medications should be made accessible to patients with HAE patients.23 "
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    ABSTRACT: Hereditary angioedema (HAE) is an autosomal dominant, potentially life-threatening condition, manifesting as recurrent and self-limiting episodes of facial, laryngeal, genital, or peripheral swelling with abdominal pain secondary to intra-abdominal edema. The estimated prevalence of HAE in the general population is one individual per 50,000, with reported ranges from 1:10,000 to 1:150,000, without major sex or ethnic differences. Various treatment options for acute attacks and prophylaxis of HAE are authorized and available in the market, including plasma-derived (Berinert®, Cinryze®, and Cetor®) and recombinant (Rhucin® and Ruconest™) C1 inhibitors, kallikrein inhibitor-ecallantide (Kalbitor®), and bradykinin B2 receptor antagonist-icatibant (Firazyr®). Some of these drugs are used only to treat HAE attacks, whereas others are only approved for prophylactic therapies and all of them have improved disease outcomes due to their different mechanisms of action. Bradykinin and its binding to B2 receptor have been demonstrated to be responsible for most of the symptoms of HAE. Thus icatibant (Firazyr®), a bradykinin B2 receptor antagonist, has proven to be an effective and more targeted treatment option and has been approved for the treatment of acute attacks of HAE. Rapid and stable relief from symptoms of cutaneous, abdominal, or laryngeal HAE attacks has been demonstrated by 30 mg of icatibant in Phase III clinical trials. Self-resolving mild to moderate local site reactions after subcutaneous injection of icatibant were observed. Icatibant is a new, safe, and effective treatment for acute attacks of HAE. HAE has been reported to result in enormous humanistic burden to patients, affecting both physical and mental health, with a negative impact on education, career, and work productivity, and with substantial economic burdens. The timely and proper use of disease-specific treatments could improve patients' quality of life, reduce the disease-specific morbidity and mortality, and, last but not least, reduce costs associated with hospitalizations and emergency room visits. Therefore, the paradigm of HAE treatment has the potential to evolve significantly, thereby exponentially improving a patient's quality of life.
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