Immune deficiencies, infection, and systemic immune disorders
Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks

https://doi.org/10.1016/j.jaci.2009.07.017Get rights and content

Background

Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder.

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

Section snippets

Study design

This multinational, parallel-group, randomized, placebo-controlled, 3-arm, double-blind, phase II/III study (with a dose-finding substudy) was conducted between August 2005 and December 2007. Our aim was to show that C1-INH shortens the time to onset of symptom relief in acute abdominal or facial HAE attacks compared with placebo and to provide a statistically secure dosing recommendation for C1-INH.

The independent ethics committee or institutional review board at each participating center

Study population

We randomized 125 patients at 36 centers worldwide to receive double-blind treatment, of whom 42 were assigned to receive placebo, 40 to receive C1-INH 10 U/kg, and 43 to receive C1-INH 20 U/kg (Fig 1).

The treatment groups were similar in terms of sex, age, and race or ethnic group (Table I). Most patients (87.1%) had type 1 HAE. Danazol was taken during the study by 14 (11.3%) patients. Overall, 98 (79.0%) patients experienced abdominal attacks, and 25 (20.2%) experienced facial attacks. One

Discussion

C1 esterase inhibitor concentrate has been in clinical use for treating acute type I and II HAE attacks since 1979. Most information on this use is based on observational studies, which have consistently reported beneficial efficacy and safety of C1-INH when treating acute HAE attacks in adults and children.29, 30, 31, 32, 33, 34 None of these studies had a randomized, placebo-controlled design to evaluate the most suitable dose of C1-INH. To address this issue, we conducted a double-blind,

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    T.J.C., R.J.L., R.L.W., A.K.B., D.H., K.O., A.R., B.R., D.M., T.S., V.G.-P., and J.A.B. received research support as investigators in this study sponsored by CSL Behring.

    Disclosure of potential conflict of interest: T. J. Craig has served as a consultant for and has received research support from Dyax, CSL Behring, Pharming, Jerini, and ViroPharma/Lev and is a board member of the American College of Allergy, Asthma & Immunology and a nominee for an Interest Section at the American Academy of Allergy, Asthma & Immunology. R. J. Levy has served as a consultant for CSL Behring, Alain, Sepracor, Dyax, and Jerini and has received research support from Grifols, CSL Behring, Pharming, Lev, Dyax Corp, AstraZeneca, Sanofi-Aventis, and Talecris. R. L. Wasserman has served as a consultant for CSL Behring. A. K. Bewtra has received research support from CSL Behring, Pfizer, Merck, and the National Institutes of Health. D. Hurewitz has served as a consultant for CSL Behring and has received research support from CSL Behring and Lev. A. Reshef has received lecture honoraria from Jerini, Germany, and CSL Behring, Germany, and has received research support from CSL Behring, Germany, Pharming, The Netherlands, and Jerini, Germany. B. Ritchie has received research support from CSL Behring and is a committee member of the Canadian Immunodeficiency Patient Organization, Medical and Scientific Advisory Committees. P. C. Kiessling is employed by CSL Behring. H.-O. Keinecke has served as a consultant for CSL Behring. J. A. Bernstein has received research support from Dyax, CSL Behring, Pharming, Jerini, and Lev. The rest of the authors have declared that they have no conflict of interest.

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