Immune deficiencies, infection, and systemic immune disorders
Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema

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Background

Hereditary angioedema (HAE) results from a genetic deficiency of C1-inhibitor. Two similar independent, randomized, saline controlled, double-blind studies were conducted to evaluate the efficacy and safety of recombinant human C1-inhibitor (rhC1INH) as a treatment of acute angioedema attacks in patients with HAE.

Objective

Analysis of pooled study results.

Methods

Patients with an eligible attack were randomized to a single intravenous dose of rhC1INH or saline. Efficacy was assessed by using patient-reported visual analog scale outcomes, and safety was assessed by using adverse events and immunogenicity of rhC1INH.

Results

rhC1INH at 100 (n = 29) and 50 (n = 12) U/kg body weight resulted in a significant reduction for both the primary endpoint time to the beginning of relief of symptoms compared with saline (n = 29): median, 66 (95% CI, 61-122) minutes, 122 (72-136) minutes, and 495 (245-520) minutes, P < .001 and P = .013, respectively; and for the secondary endpoint time to minimal symptoms, median, 266 (242-490) minutes, 247 (243-484) minutes, and 1210 (970-1500) minutes, P < .001 and P = .001, respectively. Therapeutic failure occurred in 59% (17/29) of the saline group compared with 0% (0/12) of the 50 U/kg group and 10% (3/29) of the 100 U/kg group. Treatment-emergent adverse events were unremarkable and tended to be reported more frequently in the saline group. No postexposure antibody responses against rhC1INH or host-related impurities were observed.

Conclusion

Administration of rhC1INH at 100 or 50 U/kg was highly effective as a treatment of acute attacks in patients with HAE and appeared to be safe and well tolerated.

Section snippets

Study design

C1 1205-01 and C1 1304-01 were 2 independent, randomized, saline-controlled, double-blind studies to evaluate the efficacy and clinical and laboratory safety of rhC1INH in the treatment of acute angioedema attacks in patients with HAE. The studies were similar in design, entry criteria, and endpoints. Study C1 1205-01 (clinicaltrials.gov identifier: NCT00225147) was conducted in 26 US and 4 Canadian centers (“North American”). Study C1 1304-01 (clinicaltrials.gov identifier: NCT00262301) was

Patients included

Overall, 290 patients with HAE were found to be eligible on screening (Fig 1). Seventy of these patients, 32 patients in the European study and 38 in the North American study, presented with an eligible attack and were randomized. Randomized treated patients were comparable with the nontreated eligible patients (see this article's Table E5 in the Online Repository at www.jacionline.org). The majority of nontreated eligible patients did not receive treatment because they did not present with an

Discussion

Recombinant human C1INH was developed to offer an alternative to plasma-derived C1INH for the treatment of acute angioedema attacks in patients with HAE. Two randomized, placebo-controlled studies, 1 in Europe and 1 in North America, were undertaken to evaluate the efficacy of rhC1INH as a treatment for acute angioedema attacks in patients with HAE. Both studies had similar protocols, and both studies included fewer patients than foreseen because they both were stopped when a predefined interim

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    • Cited by (0)

    Supported by Pharming Technologies BV, Leiden, The Netherlands. Additional funding for the North American study was provided by US Food and Drug Administration Office of Orphan Products Development grant 1-R01-FD-R 03086-01.

    Disclosure of potential conflict of interest: B. Zuraw is a consultant for ViroPharma, CSL Behring, and Shire; has received research support from Pharming; and is an advisor for the HAE Association. M. Cicardi has received honoraria from Dyax, Jerini-Shire, and ViroPharma and is a consultant for Dyax. R. J. Levy is a medical consultant for CSL Behring, Dyax Corp, and Jerini and has received research support from CSL Behring, Dyax Corp, and Lev Pharma. G. Haase has received independent consulting fees from Pharming Technologies BV. L. Kaufman is a consultant for Pharming and has served as an expert witness on the topic of statistical analysis. C. E. Hack has received a consultancy fee from Pharming Technologies BV. The rest of the authors have declared that they have no conflict of interest.

    ∗

    These authors contributed equally to this work.

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