Original Article
Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary Angioedema
N Engl J Med 2010; 363:513-522August 5, 2010
- Abstract
Background
Hereditary angioedema due to C1 inhibitor deficiency is characterized by recurrent acute attacks of swelling that can be painful and sometimes life-threatening.
Methods
We conducted two randomized trials to evaluate nanofiltered C1 inhibitor concentrate in the management of hereditary angioedema. The first study compared nanofiltered C1 inhibitor concentrate with placebo for treatment of an acute attack of angioedema. A total of 68 subjects (35 in the C1 inhibitor group and 33 in the placebo group) were given one or two intravenous injections of the study drug (1000 units each). The primary end point was the time to the onset of unequivocal relief. The second study was a crossover trial involving 22 subjects with hereditary angioedema that compared prophylactic twice-weekly injections of nanofiltered C1 inhibitor concentrate (1000 units) with placebo during two 12-week periods. The primary end point was the number of attacks of angioedema per period, with each subject acting as his or her own control.
Results
In the first study, the median time to the onset of unequivocal relief from an attack was 2 hours in the subjects treated with C1 inhibitor concentrate but longer than 4 hours in those given placebo (P=0.02). In the second study, the number of attacks per 12-week period was 6.26 with C1 inhibitor concentrate given as prophylaxis, as compared with 12.73 with placebo (P<0.001); the subjects who received the C1 inhibitor concentrate also had significant reductions in both the severity and the duration of attacks, in the need for open-label rescue therapy, and in the total number of days with swelling.
Conclusions
In subjects with hereditary angioedema, nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks. When used for prophylaxis, nanofiltered C1 inhibitor concentrate reduced the frequency of acute attacks. (Funded by Lev Pharmaceuticals; ClinicalTrials.gov numbers, NCT00289211, NCT01005888, NCT00438815, and NCT00462709.)
Media in This Article
Figure 1
Primary Outcome in the Trial of C1 Inhibitor Therapy for Acute Attacks of Angioedema.Figure 2
Normalized Rate of Angioedema Attacks during the Prophylaxis Trial.Article Activity
- Article
Hereditary angioedema due to C1 inhibitor deficiency is an autosomal dominant disorder characterized by recurrent episodes of angioedema that typically involve the extremities, abdomen, external genitalia, face, or oropharynx. 1 Abdominal attacks of angioedema, which are caused by local mucosal swelling, are often associated with severe abdominal pain, nausea, and vomiting. Such attacks frequently lead to hospitalization and occasionally to unnecessary exploratory surgery.2 Laryngeal attacks are associated with a substantial risk of death.2
Two forms of hereditary angioedema have been defined: type I (accounting for 85% of cases) is characterized by low antigenic and functional levels of C1 inhibitor, whereas type II (15% of cases) is characterized by normal antigenic levels of C1 inhibitor but low functional levels.3,4, Both types are due to mutations in the C1 inhibitor gene. 5-8
Anabolic androgens and antifibrinolytic drugs are used for the prophylactic management of hereditary angioedema,9,10 but these agents may be associated with clinically significant adverse effects.11,12 C1 inhibitor concentrates have been shown to be effective in the treatment of acute attacks in patients with hereditary angioedema,13-19 and their use is supported by the results of randomized trials18,19 and by published consensus statements.20,21
A nanofiltered C1 inhibitor concentrate (Cinryze, ViroPharma) has recently been developed. We report the results of two randomized trials of nanofiltered C1 inhibitor concentrate for the management of hereditary angioedema, one study to evaluate its use in acute attacks and the other its use as prophylaxis.
Methods
Study Oversight
Both double-blind, placebo-controlled trials were designed by the principal investigator and approved by the appropriate institutional review board for each participating site. The studies were sponsored by Lev Pharmaceuticals (now owned by ViroPharma Biologics). The investigators at each of the participating centers conducted the studies and collected the data with the assistance of a contract research organization. Data analysis was performed by the investigators with the assistance of consulting statisticians hired by Lev Pharmaceuticals. The sponsor and its representatives had no role in the study design, data collection or analysis, or decisions concerning submission of the data for publication. All the authors contributed to the writing of the manuscript and vouch for the accuracy and completeness of the data and analyses as well as the fidelity of the report to the study protocol. The trial protocol is available with the full text of this article at NEJM.org.
Study Participants
Participants in both studies were required to be at least 6 years of age and to have a confirmed diagnosis of hereditary angioedema, including a low C4 level, a normal C1q level, and a low antigenic or functional C1 inhibitor level or a mutation in the C1 inhibitor gene known to cause hereditary angioedema. Exclusion criteria included a low C1q level, a history of a B-cell cancer, the presence of anti–C1 inhibitor antibody, a history of allergic reaction to C1 inhibitor or other blood or plasma products, pregnancy, and narcotic addiction. Subjects were not required to change any of their regular medications, including androgens or antifibrinolytic drugs. All participants provided written informed consent.
Nanofiltered C1 Inhibitor Concentrate
The C1 inhibitor concentrate was prepared by Sanquin in the Netherlands with the use of plasma obtained in the United States. Briefly, C1 inhibitor was purified by a combination of cryoprecipitation, ion-exchange chromatography, and polyethylene glycol precipitation. The resulting C1 inhibitor fraction was pasteurized, double-nanofiltered with the use of 15-nm Planova filters (Asahi Kasei Medical), and lyophilized.
Study Design
Treatment of Acute Attacks
For the acute-attack treatment study, eligible subjects were enrolled and then asked to return to the study site within 4 hours after the onset of an acute attack. (See Fig. 1A in the Supplementary Appendix, available at NEJM.org.) Study personnel were available at all times, and subjects who presented with an acute attack were assessed on the basis of additional criteria to determine whether the attack itself qualified for trial eligibility. Attacks were excluded if the subject had used narcotics within the previous 7 days or had increased the use of anabolic androgens within the previous 5 days. Attacks of laryngeal angioedema were also excluded, and subjects with such attacks were treated with open-label nanofiltered C1 inhibitor concentrate. In addition, subjects were asked to rate their angioedema symptoms as none, mild, moderate, or severe for each affected site (extremities, throat, abdomen, face, and external genitalia). Only subjects with attacks of moderate or severe intensity that involved the abdomen, face, or external genitalia were eligible for randomized treatment. The site of the most severe symptoms was designated the “defining site.”
Subjects who were eligible for participation in the acute-attack treatment trial on the basis of these criteria were randomly assigned to receive either C1 inhibitor concentrate (1000 units in 10 ml of sterile water) or placebo (10 ml of saline) administered by intravenous push over a 10-minute period. Subjects were asked to report the severity of symptoms at each involved site with the use of the following descriptions: absent now and absent before; absent now but present before; present, symptoms new; present, symptoms worse or the same; or present, symptoms better.17 If the subject did not report that symptoms at the defining site were either absent or better by 60 minutes after the initial injection of the study drug (C1 inhibitor or placebo), a second injection of the same study drug was administered.
Symptom severity was assessed every 15 minutes, beginning with the initial injection and continuing until the subject reported unequivocal relief at the defining site, with unequivocal relief defined as three consecutive reports of improvement at that site. If 4 hours elapsed without unequivocal relief, the assessments were discontinued, and rescue therapy with open-label C1 inhibitor was offered. Subjects were subsequently contacted by telephone to confirm the complete resolution of symptoms and were asked to return for a follow-up office visit at 3 months. Levels of C1 inhibitor and C4 were measured before the infusion and 60 minutes, 2 hours, and 4 hours after the infusion.
The primary end point was the time from administration of the study drug to unequivocal relief of symptoms at the defining site (i.e., the first of three consecutive reports of improvement). Secondary efficacy end points included the percentage of subjects who had an onset of unequivocal relief within 4 hours after treatment, the time to complete resolution of the attack (i.e., all symptoms of swelling absent), and the effects of treatment on antigenic and functional levels of C1 inhibitor and on C4 levels. Safety was evaluated by assessing adverse events, changes in clinical laboratory values, physical findings, and vital signs before and after the injection.
A blinded review of all screening and pretreatment C4 values was performed after the subjects completed the study treatment. If the C4 level was not reduced when the subject presented with an attack, all clinical information and laboratory data that had been available before treatment were sent to an independent expert (Dr. M. Cicardi, Milan) for further blinded review to determine whether the episode was likely to have been a true attack of angioedema.
Prophylaxis
In the prophylaxis study, nanofiltered C1 inhibitor concentrate was compared with placebo for preventing attacks of angioedema during a 24-week crossover period. Subjects who had been randomly assigned to a study drug in the acute-attack treatment study and who also had a history of at least two attacks per month were eligible to participate in the prophylaxis study (Fig. 1B in the Supplementary Appendix). Subjects were not allowed to change their prophylactic androgen or antifibrinolytic medications during or for 30 days before the prophylaxis study.
This study consisted of two consecutive 12-week treatment periods during which subjects received prophylactic injections every 3 to 4 days. Subjects were randomly assigned to receive either C1 inhibitor concentrate (1000 units in 10 ml of sterile water) or placebo (10 ml of saline) during the first period. During the second period, they received the study medication that had not been assigned during the first period. Subjects were asked to keep a daily diary of symptoms throughout both study periods. All subjects with acute attacks of angioedema were eligible for rescue treatment with open-label C1 inhibitor. Prophylactic study injections were delayed for at least 24 hours after open-label rescue treatment for an acute attack.
The primary efficacy end point for the prophylactic study was the number of attacks of angioedema during each treatment period, which we normalized for the number of days the subject participated during that period. We did this by dividing the total number of attacks in each period by the number of days the subject participated during that period and multiplying the resulting number of attacks per day by 84 (7×12) to yield the number of attacks per 12-week period. Secondary end points, reported for each period, included the average severity of attacks, average duration of attacks, number of open-label injections of C1 inhibitor, and total number of days of swelling. In addition, changes from baseline in antigenic and functional levels of C1 inhibitor were evaluated. Safety assessments included the extent of exposure; the number and severity of adverse events; and changes in clinical laboratory values, vital signs, and findings on physical examination, as determined every 3 months during the study.
Subjects who participated in and completed one or both of these randomized studies were eligible to enroll in a subsequent open-label extension trial.
Statistical Analysis
For the acute-attack treatment study, the primary outcome variable was the time to the onset of unequivocal relief. The between-group comparison was performed by means of a Cox proportional-hazards regression model, with the use of the exact method for handling tied-event times and with the centers included in the model as indicator covariates. Results from the sites that had no subjects in one of the treatment groups were pooled for all analyses. Hazard ratios and their 95% confidence intervals were estimated and referred to as success ratios, since the event of primary interest in this study was improvement. The need for rescue medication (i.e., narcotics or open-label C1 inhibitor administration) within 4 hours of the study drug injection was considered a treatment failure as well as a competing event, because such rescue interventions precluded observation of the event of interest. Data for subjects who did not have an onset of unequivocal relief of symptoms by 4 hours after treatment were censored at 4 hours. The estimated median time to the onset of unequivocal relief was calculated by means of a cumulative incidence method, since rescue therapy administered before 4 hours was considered a competing event.22 Categorical variables were compared between the two treatment groups by means of the Cochran–Mantel–Haenszel test stratified by study site.
For the prophylaxis study, the primary end point was the attack rate (normalized to 12 weeks) during the administration of C1 inhibitor minus the attack rate during the administration of placebo. A generalized-estimating-equation analysis of variance for the crossover study design was performed on the basis of a Poisson assumption, with effects for treatment sequence, treatment period, and subjects within sequence; each subject served as his or her own control.23 All subjects who completed the entire initial study period and who received at least one study injection during the crossover period were included in the analysis. Secondary end points were analyzed by means of the Wilcoxon signed-rank test.
All significance tests for both studies were two-sided, with a P value of less than 0.05 considered to indicate statistical significance. Analyses and summaries were produced with the use of SAS software (version 8.2, SAS Institute).
Results
Acute-Attack Treatment Trial
From March 14, 2005, through May 18, 2007, a total of 324 subjects were screened at 37 study sites (Fig. 1A in the Supplementary Appendix), and 207 subjects were considered eligible for trial participation. Of this group, 71 presented with attacks and were randomly assigned to receive either C1 inhibitor (36 subjects) or placebo (35 subjects). After completion of the study treatment, 3 subjects (1 in the C1 inhibitor group and 2 in the placebo group) were judged by an independent, blinded expert to have had episodes that were not true attacks of angioedema. These subjects were therefore excluded from the efficacy analysis. Table 1Table 1
Baseline Characteristics of the Subjects in the Acute-Attack Treatment Trial and the Prophylaxis Trial. shows the baseline characteristics of the remaining 68 subjects.The estimated median time to the onset of unequivocal relief was 2 hours in the C1 inhibitor group, as compared with more than 4 hours in the placebo group (estimated success rate ratio, 2.41; 95% confidence interval [CI], 1.17 to 4.95; P=0.02). There was no evidence of heterogeneity according to study site, body-mass index, sex, time from the onset of an attack to randomization, or defining attack site (Part 2A in the Supplementary Appendix). When the three subjects who were judged not to have had true attacks of angioedema were included in the primary end-point analysis, the C1 inhibitor group still had a significant benefit with respect to the time to the onset of unequivocal relief (estimated success ratio, 2.05; 95% CI, 1.01 to 4.16; P=0.048).
The onset of unequivocal relief occurred within 4 hours in 21 of the 35 subjects in the C1 inhibitor group and in 14 of the 33 subjects in the placebo group (60% vs. 42%, P=0.06) (Figure 1Figure 1
Primary Outcome in the Trial of C1 Inhibitor Therapy for Acute Attacks of Angioedema.). A second dose of the blinded study drug was administered to 23 subjects in the C1 inhibitor group and to 28 patients in the placebo group (Part 2B in the Supplementary Appendix). The median time to complete resolution of symptoms was 12.3 hours in the C1 inhibitor group and 25.0 hours in the placebo group (P=0.004), even though all subjects who did not have substantial improvement by the end of the 4-hour assessment period were given open-label C1 inhibitor. Both antigenic and functional levels of C1 inhibitor increased significantly during treatment in the group given C1 inhibitor but not in the group given placebo (P<0.001 for both between-group comparisons). In contrast, C4 levels did not change significantly during the period of observation (i.e., the first 4 hours) (P=0.86 for the between-group comparison) (Part 2C in the Supplementary Appendix).Prophylaxis Trial
Of the 71 subjects randomly assigned to a study group in the acute-attack treatment trial, 24 were enrolled in the prophylaxis trial and were randomly assigned to one of two groups: 12 to placebo and 12 to C1 inhibitor for the first of two 12-week periods (Fig. 1B in the Supplementary Appendix). During the first period, one subject from each group withdrew, leaving 22 subjects (11 in each group) who completed the first period and then crossed over to the other study treatment for the second period. The results for both periods were included in the end-point analyses (Fig. 1B in the Supplementary Appendix). Although included in the analysis, 2 of the 22 subjects (1 in each group) did not complete the second 12-week period.
The average normalized attack rates for all 22 subjects during the two 12-week crossover periods were 6.26 and 12.73 attacks for the C1 inhibitor and placebo treatments, respectively (Figure 2Figure 2
Normalized Rate of Angioedema Attacks during the Prophylaxis Trial.). The estimated average difference in attack rates between subjects receiving C1 inhibitor and those receiving placebo was 6.47 attacks (95% CI, 4.21 to 8.73; P<0.001), and there was no evidence of a significant sequence effect (P=0.54) or period effect (P=0.42). The mean (±SD) score for the severity of attacks (on a 3-point scale, with 1 indicating mild, 2 moderate, and 3 severe) was significantly lower with C1 inhibitor prophylaxis than with placebo (1.3±0.85 vs. 1.9±0.36, P<0.001) (Figure 3Figure 3
Major Events during the Prophylaxis Trial.). Likewise, the total duration of attacks was significantly shorter with C1 inhibitor prophylaxis than with placebo (2.1±1.13 vs. 3.4±1.39 days, P=0.002). A total of 11 subjects receiving C1 inhibitor prophylaxis required open-label rescue therapy, as compared with 22 subjects receiving placebo. C1 inhibitor prophylaxis was associated with fewer open-label injections (4.7±8.66 vs. 15.4±8.41, P<0.001) and fewer days of swelling (10.1±10.73 vs. 29.6±16.9, P<0.001).Open-Label Treatment Extension
After the two trials were completed, 88 subjects chose to enroll in an open-label extension study for the treatment of acute attacks. At a median of 11 months, 82 of the enrolled subjects had received open-label C1 inhibitor treatment for a total of 447 separate attacks, with the number of attacks per subject ranging from 1 to 57 (median, 3). The median time to a response for the 447 attacks was 30 minutes, irrespective of whether a subject was given open-label treatment fewer than 4 times, 4 to 9 times, or 10 times or more. The Kaplan–Meier estimate of the proportion of attacks that responded to treatment within 4 hours was 93%.
Adverse Events
During the acute-attack treatment trial, 6 of the 36 subjects randomly assigned to C1 inhibitor (17%) and 7 of the 35 subjects randomly assigned to placebo (20%) had adverse events (Table 2Table 2
Adverse Events in the Acute-Attack Treatment Trial and the Prophylaxis Trial.). Only 3 of these events were classified as possibly related to the study drug (in the placebo group, tetany [carpal tunnel spasm] in 1 subject and contact dermatitis in 1 subject; in the C1 inhibitor group, rash at the injection site in 1 subject). In the prophylaxis trial, 21 of 24 subjects (88%) had one or more adverse events (Part 3 in the Supplementary Appendix). Three adverse events (pruritus and rash, lightheadedness, and fever) were classified as possibly related to the study drug (Table 2).Discussion
The use of C1 inhibitor replacement therapy for the treatment of acute attacks in subjects with hereditary angioedema was first reported 30 years ago.16 A number of subsequent studies have also shown a beneficial effect of such therapy,13-15 including two placebo-controlled trials.18,19 In countries where C1 inhibitor replacement therapy is available, consensus statements affirm its use as the standard of care for acute attacks of hereditary angioedema.20,21
In our acute-attack treatment trial, nanofiltered C1 inhibitor concentrate significantly reduced the time to the onset of unequivocal relief of symptoms as compared with placebo. However, 40% of subjects treated with C1 inhibitor did not have an onset of unequivocal relief of symptoms within 4 hours. This failure rate is higher than that reported in the two previous randomized trials,18,19 although the study design and analysis differed somewhat from those of our trial. For example, the trial reported by Craig et al.19 had a failure rate at 4 hours of approximately 15% for high-dose C1 inhibitor therapy and approximately 27% for low-dose therapy. However, in that study, the response to placebo at 4 hours was also higher (60%, as compared with 42% in our study).
We also conducted an open-label assessment of nanofiltered C1 inhibitor concentrate for treatment of acute attacks. In this analysis, symptoms improved within 4 hours in 93% of 447 treatments. The efficacy of C1 inhibitor for the treatment of acute attacks of angioedema is greater in open-label trials than in placebo-controlled trials, both in our experience and in that of other investigators. Psychological factors such as the fear of receiving placebo for the treatment of severe abdominal pain are likely to have influenced both the severity and the number of attacks.24
Subjects with hereditary angioedema who are at high risk for acute attacks require prophylactic treatment. Short-term prophylaxis is routinely given before dental procedures or other situations likely to precipitate an acute attack, and C1 inhibitor replacement, in the form of either fresh-frozen plasma or C1 inhibitor concentrate, has been shown to be effective for this purpose.25,26 There are also anecdotal reports of C1 inhibitor concentrate being given intravenously for long-term prophylaxis.15,27,28 In a crossover study, Waytes et al. found that prophylactic treatment with vapor-heated C1 inhibitor every 3 days for 17 days decreased angioedema symptoms in six subjects by approximately 60% as compared with placebo.18 In our prophylaxis crossover trial, nanofiltered C1 inhibitor concentrate significantly reduced the frequency of acute attacks as compared with placebo over a 12-week period.
Both studies presented here used a fixed dose of nanofiltered C1 inhibitor concentrate. Most of the participants in the acute-attack treatment trial required a second injection of the study drug. In the prophylaxis trial, C1 inhibitor therapy reduced the number of open-label injections to a mean of 4.7 over a period of 12 weeks. In both studies, the need for additional, rescue injections suggests that in some cases a higher dose or more frequent injections of C1 inhibitor might have been beneficial. Thus, the optimal dose of nanofiltered C1 inhibitor concentrate for either treatment or prophylaxis remains uncertain.
Since C1 inhibitor formulations are prepared from human plasma, the risk of viral contamination is an ongoing concern. Other C1 inhibitor concentrates undergo multiple steps to inactivate viruses, including pasteurization.25 The use of nanofiltration along with pasteurization of the preparations used in our study provided an additional level of safety based on exclusion by size, which may be particularly important for protection against nonenveloped viruses and new infectious agents, such as prions.29
In summary, we evaluated a recently developed formulation of C1 inhibitor concentrate in two randomized trials for the management of hereditary angioedema due to C1 inhibitor deficiency. During acute attacks, nanofiltered C1 inhibitor concentrate significantly reduced the time to unequivocal relief of symptoms, as compared with placebo. When used for prophylaxis, C1 inhibitor significantly reduced the frequency of acute attacks, as compared with placebo.
Supported by grants from Lev Pharmaceuticals (now owned by ViroPharma Biologics).
Dr. Zuraw reports receiving consulting fees from Lev Pharmaceuticals, CSL Behring, Jerini (now Shire), and Dyax; reimbursements for travel or accommodation expenses from Lev Pharmaceuticals, Shire, and Dyax; fees for serving on the speakers bureau of the Robert Michael Educational Institute; grant support from Lev Pharmaceuticals, Pharming, and Shire; and fees for providing expert testimony for Lev Pharmaceuticals; Dr. Busse, receiving consulting fees and reimbursements for travel or accommodation expenses from Lev Pharmaceuticals; grant support from Lev Pharmaceuticals and Shire Pharmaceuticals; fees for reviewing a patient file from Eichorn and Eichorn; payment for manuscript preparation from Innovative Strategic Communications; and fees for serving on the speakers bureaus of ViroPharma and the Robert Michael Educational Institute; Dr. White, receiving consulting fees from Lev Pharmaceuticals and Dyax; reimbursements for travel or accommodation expenses from Dyax; honoraria from Dyax; grant support from Lev Pharmaceuticals, Dyax, Shire, ViroPharma, and Pharming; and fees for serving on the speakers bureau of ViroPharma; Dr. Jacobs, receiving consulting fees from ViroPharma; reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and ViroPharma; honoraria from ViroPharma; grant support from Lev Pharmaceuticals; and fees for serving on the speakers bureaus of ViroPharma and Lev Pharmaceuticals; Dr. Lumry, receiving consulting fees and honoraria from ViroPharma; consulting fees from Dyax and Shire; reimbursements for travel or accommodation expenses from ViroPharma, Dyax, and Shire; grant support from Lev Pharmaceuticals, Dyax, and Shire; and payment for development of educational presentations from Dyax; Dr. Baker, receiving grant support from Lev Pharmaceuticals, Shire, Dyax, and Pharming; Dr. Craig, receiving consulting fees from ViroPharma, Dyax, and CSL Behring; fees for participation in review activities and reimbursements for travel or accommodation expenses from ViroPharma; honoraria from ViroPharma, Dyax, and CSL Behring; grant support from Lev Pharmaceuticals, ViroPharma, Dyax, CSL Behring, Pharming, and Shire; and payment for development of educational presentations from Dyax, CSL Behring, and ViroPharma; Dr. Grant, receiving reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and Dyax and grant support from Lev Pharmaceuticals, Dyax, and Shire; Dr. Hurewitz, receiving consulting fees from Shire; reimbursements for travel or accommodation expenses from ViroPharma, Shire, Dyax, and CSL Behring; honoraria from Shire; and grant support from Lev Pharmaceuticals, ViroPharma, Shire, Dyax, and CSL Behring; Dr. Bielory, receiving reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and grant support from Lev Pharmaceuticals and STARx Clinical Research Center; Dr. Cartwright, receiving grant support and consulting fees or honoraria from Lev Pharmaceuticals and ViroPharma; Dr. Koleilat, receiving grant support from Lev Pharmaceuticals; Dr. Ryan, receiving grant support from Lev Pharmaceuticals; Dr. Schaefer, receiving grant support from Lev Pharmaceuticals and reimbursements for travel or accommodation expenses from ViroPharma; Dr. Manning, receiving reimbursements for travel or accommodation expenses and grant support from Lev Pharmaceuticals and ViroPharma; honoraria from ViroPharma; and payment for development of educational presentations from ViroPharma; Dr. Patel, receiving grant support from Lev Pharmaceuticals; Dr. Bernstein, receiving consulting fees from Dynova, Lantheus, and Flint Hills Resources; honoraria from AstraZeneca, Alcon Labs, Dyax, ViroPharma, and CSL Behring; fees for providing expert testimony on environmental and drug reaction cases; and grant support from Lev Pharmaceuticals, Dyax, ViroPharma, CSL Behring, Shire, Pharming, Dynova, and Flint Hills Resources; and being listed as a patent holder on a patent held by the University of Cincinnati for a biosensor to detect airborne chemicals from Biosensors; Dr. Friedman, receiving reimbursements for travel or accommodation expenses from ViroPharma and grant support from Lev Pharmaceuticals; Dr. Wilkinson, receiving fees for study visits from Lev Pharmaceuticals and grant support from Dyax; Dr. Tanner, receiving grant support from Lev Pharmaceuticals; Dr. Gunther, receiving grant support from Lev Pharmaceuticals; Dr. Levy, receiving grant support from Lev Pharmaceuticals and ViroPharma; consulting fees from CSL Behring, Alcon Labs, Dyax, Jerini, and Sepracor; reimbursements for travel or accommodation expenses from CSL Behring and Dyax; and payment for manuscript preparation from Cadent Communications; Dr. McClellan, receiving a grant from Lev Pharmaceuticals; Dr. Redhead, receiving a grant from Lev Pharmaceuticals; Dr. Guss, receiving grant support from Lev Pharmaceuticals; Dr. Heyman, receiving consulting fees from Lev Pharmaceuticals; Dr. Blumenstein, receiving consulting fees and reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and ViroPharma; Dr. Kalfus, receiving consulting fees and reimbursements for travel or accommodation expenses from Lev Pharmaceuticals and ViroPharma; payment for development of educational presentations from ViroPharma; and stocks and stock options from Lev Pharmaceuticals; and being previously employed as vice president of medical affairs at Lev Pharmaceuticals; and Dr. Frank, receiving consulting fees from ViroPharma, CSL Behring, Shire, Dyax, and Pharming; fees for providing expert testimony for Lev Pharmaceuticals, Jerini, and CSL Behring; reimbursements for travel or accommodation expenses from ViroPharma; and grant support from Lev Pharmaceuticals and CSL Behring. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the patients who participated in this study and the U.S. Hereditary Angioedema Association for referring subjects to the study.
Source Information
Authors' affiliations are listed in the Appendix.
Address reprint requests to Dr. Zuraw at 9500 Gilman Dr., Mailcode 0732, La Jolla, CA 92093-0732, or at bzuraw@ucsd.edu.
Appendix
The authors' affiliations are as follows: the University of California, San Diego (B.L.Z., D.G.), San Diego Veterans Affairs Healthcare System, La Jolla (B.L.Z.), and Allergy and Asthma Clinical Research, Walnut Creek (J.J.) — all in California; Mt. Sinai School of Medicine (P.J.B.) and M2G Consulting and Lev Pharmaceuticals (I.K.) — both in New York; Institute for Asthma and Allergy, Wheaton (M.W.), and ERHStats, Montgomery Village (E.H.) — both in Maryland; Asthma and Allergy Research Associates, Dallas (W.L.), and University of Texas Medical Branch, Galveston (J.A.G.) — both in Texas; Allergy, Asthma, and Dermatology Research Center, Lake Oswego, OR (J.B.); Penn State University, Hershey, PA (T.C.); Allergy Clinic of Tulsa, Tulsa, OK (D.H.); University of Medicine and Dentistry of New Jersey, Newark (L.B.); Cornerstone Healthcare–St. Joseph's Healthcare System, Parkersburg, WV (W.E.C.); Welborn Clinic, Evansville, IN (M.K.); Allergy and Asthma Center, Falmouth (W.R.), and the University of Massachusetts, Worcester (O.S.) — both in Massachusetts; Allergy and Immunology Associates, Scottsdale, AZ (M.M.); Allergy Asthma Specialists, Altamonte Springs, FL (P.P.); University of Cincinnati, Cincinnati (J.A.B.), and Buckeye Allergy and Asthma, Columbus (R.A.F.) — both in Ohio; Hawaii Pacific Health Research Institute, Honolulu (R.W.); Atlanta Allergy and Asthma Clinic, Suwanee (D.T.), and Family Allergy and Asthma Center, Atlanta (R.L.) — both in Georgia; Lake Charles Memorial Hospital, Lake Charles (G.K.), and Baton Rouge Clinic, Baton Rouge (J.R.) — both in Louisiana; Libby Clinic, Libby, MT (G.G.); Grand Traverse Allergy, Traverse City, MI (J.M.); Trial Architecture Consulting, Washington, DC (B.A.B.); and Duke University, Durham, NC (M.M.F.).
- References
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- Citing Articles (34)
Citing Articles
1
Anurag Relan, Kamran Bakhtiari, Edwin S. van Amersfoort, Joost C.M. Meijers, C. Erik Hack. (2012) Recombinant C1-Inhibitor. BioDrugs 26:1, 43-52
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M. Cicardi, K. Bork, T. Caballero, T. Craig, H. H. Li, H. Longhurst, A. Reshef, B. Zuraw, . (2012) Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 67:2, 147-157
CrossRef3
Hilary Longhurst, Marco Cicardi. (2012) Hereditary angio-oedema. The Lancet 379:9814, 474-481
CrossRef4
Leslie E Stolz, Albert L Sheffer. (2012) Prospective, double-blind, placebo-controlled trials of ecallantide for acute attacks of hereditary angioedema. Expert Review of Clinical Immunology 8:1, 25-32
CrossRef5
C. E. Hack, A. Relan, E. S. van Amersfoort, M. Cicardi. (2012) Target levels of functional C1-inhibitor in hereditary angioedema. Allergy 67:1, 123-130
CrossRef6
L. Bouillet. (2012) L’angiœdème héréditaire : une révolution thérapeutique. La Revue de Médecine Interne
CrossRef7
Thomas Renné. (2012) The procoagulant and proinflammatory plasma contact system. Seminars in Immunopathology 34:1, 31-41
CrossRef8
Marc A. Riedl, David S. Hurewitz, Robyn Levy, Paula J. Busse, David Fitts, Ira Kalfus. (2012) Nanofiltered C1 esterase inhibitor (human) for the treatment of acute attacks of hereditary angioedema: an open-label trial. Annals of Allergy, Asthma & Immunology 108:1, 49-53
CrossRef9
Moonjung Jung, Lawrence Rice. (2011) “Surgical” Abdomen in a Patient with Chronic Lymphocytic Leukemia: A Case of Acquired Angioedema. Journal of Gastrointestinal Surgery 15:12, 2262-2266
CrossRef10
Teresa Caballero, Henriette Farkas, Laurence Bouillet, Tom Bowen, Anne Gompel, Christina Fagerberg, Janne Bjökander, Konrad Bork, Anette Bygum, Marco Cicardi, Caterina de Carolis, Michael Frank, Jimmy H.C. Gooi, Hilary Longhurst, Inmaculada Martínez-Saguer, Erik Waage Nielsen, Krystina Obtulowitz, Roberto Perricone, Nieves Prior. (2011) International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. Journal of Allergy and Clinical Immunology
CrossRef11
Mili Shum, Sunit P. Jariwala, David Rosenstreich. (2011) Successful C1 inhibitor prophylaxis during zenker diverticulum repair in a patient with hereditary angioedema. Annals of Allergy, Asthma & Immunology
CrossRef12
Marco Cicardi, Massimo Cugno. 2011. 18 Kallikrein-kinin system in angioedema. , 289-306.
CrossRef13
J.J. Hofstra, I. Kleine Budde, E. van Twuyver, G. Choi, M. Levi, F.W.G. Leebeek, J.G.R. de Monchy, P.F. Ypma, R.J. Keizer, A.D.R. Huitema, P.F.W. Strengers. (2011) Treatment of hereditary angioedema with nanofiltered C1-esterase inhibitor concentrate (Cetor®): Multi-center phase II and III studies to assess pharmacokinetics, clinical efficacy and safety. Clinical Immunology
CrossRef14
Konrad Bork. (2011) Human pasteurized C1-inhibitor concentrate for the treatment of hereditary angioedema due to C1-inhibitor deficiency. Expert Review of Clinical Immunology 7:6, 723-733
CrossRef15
Katherine A. Lyseng-Williamson. (2011) Nanofiltered Human C1 Inhibitor Concentrate (Cinryze®). BioDrugs 25:5, 317-327
CrossRef16
Louanne Marie Tourangeau, Bruce L. Zuraw. (2011) The New Era of C1-Esterase Inhibitor Deficiency Therapy. Current Allergy and Asthma Reports 11:5, 345-351
CrossRef17
Mark M Gompels, Robert John Lock. (2011) Cinryze™ (C1-inhibitor) for the treatment of hereditary angioedema. Expert Review of Clinical Immunology 7:5, 569-573
CrossRef18
T. J. Craig, A. K. Bewtra, S. L. Bahna, D. Hurewitz, L. C. Schneider, R. J. Levy, J. N. Moy, J. Offenberger, K. W. Jacobson, W. H. Yang, F. Eidelman, G. Janss, F. R. Packer, M. A. Rojavin, T. Machnig, H.-O. Keinecke, R. L. Wasserman. (2011) C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks - final results of the I.M.P.A.C.T.2 study. Allergyno-no
CrossRef19
Shayna Burke, Andrej Petrov, Jonas Johnson, Andrew MacGinnitie. (2011) Successful use of ecallantide to treat a hereditary angioedema attack after failure of C1 inhibitor prophylaxis. Annals of Allergy, Asthma & Immunology 107:2, 181-182
CrossRef20
Neil Parikh, Marc A. Riedl. (2011) New Therapeutics in C1INH Deficiency: A Review of Recent Studies and Advances. Current Allergy and Asthma Reports 11:4, 300-308
CrossRef21
B. Floccard, J. Crozon, T. Rimmelé, A. Vulliez, B. Coppere, V. Chamouard, I. Boccon-Gibod, L. Bouillet, B. Allaouchiche. (2011) Prise en charge en urgence de l’angiœdème à bradykinine. Annales Françaises d'Anesthésie et de Réanimation 30:7-8, 578-588
CrossRef22
Stephen A. Tilles, Larry Borish. (2011) A new generation of hereditary angioedema treatments: remarkable advances clash with disturbing economic reality. Annals of Allergy, Asthma & Immunology 106:4, 264-266
CrossRef23
Allen P. Kaplan. (2011) Bradykinin and the Pathogenesis of Hereditary Angioedema. World Allergy Organization Journal 4:4, 73-75
CrossRef24
Lilian Varga, Henriette Farkas. (2011) rhC1INH: a new drug for the treatment of attacks in hereditary angioedema caused by C1-inhibitor deficiency. Expert Review of Clinical Immunology 7:2, 143-153
CrossRef25
Neelu Kalra, Timothy Craig. (2011) Update on recent trials in the treatment of hereditary angioedema. Clinical Investigation 1:3, 439-445
CrossRef26
Marcus Maurer, Markus Magerl. (2011) Long-term prophylaxis of hereditary angioedema with androgen derivates: a critical appraisal and potential alternatives. JDDG: Journal der Deutschen Dermatologischen Gesellschaft 9:2, 99-107
CrossRef27
Richard G. Gower, Paula J. Busse, Emel Aygören-Pürsün, Amin J. Barakat, Teresa Caballero, Mark Davis-Lorton, Henriette Farkas, David S. Hurewitz, Joshua S. Jacobs, Douglas T. Johnston, William Lumry, Marcus Maurer. (2011) Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on Prophylaxis Treatment Strategies. World Allergy Organization Journal 4:2, S9-S21
CrossRef28
(2011) Therapeutic Agents for Hereditary Angioedema. New England Journal of Medicine 364:1, 84-86
Full Text29
Tom Bowen. (2011) Hereditary angioedema: beyond international consensus - circa December 2010 - The Canadian Society of Allergy and Clinical Immunology Dr. David McCourtie Lecture. Allergy, Asthma & Clinical Immunology 7:1, 1
CrossRef30
Richard L. Wasserman, Robyn J. Levy, Againdra K. Bewtra, David Hurewitz, Timothy J. Craig, Peter C. Kiessling, Heinz-Otto Keinecke, Jonathan A. Bernstein. (2011) Prospective study of C1 esterase inhibitor in the treatment of successive acute abdominal and facial hereditary angioedema attacks. Annals of Allergy, Asthma & Immunology 106:1, 62-68
CrossRef31
Rafael Firszt, Michael M. Frank. (2010) An Overview of Novel Therapies for Acute Hereditary Angioedema. American Journal of Clinical Dermatology 11:6, 383-388
CrossRef32
Allen P. Kaplan. (2010) Enzymatic pathways in the pathogenesis of hereditary angioedema: The role of C1 inhibitor therapy. Journal of Allergy and Clinical Immunology 126:5, 918-925
CrossRef33
Michael M. Frank. (2010) Recombinant and Plasma-Purified Human C1 Inhibitor for the Treatment of Hereditary Angioedema. World Allergy Organization Journal 3:Supplement, S29-S33
CrossRef34
Morgan, B. Paul, . (2010) Hereditary Angioedema — Therapies Old and New. New England Journal of Medicine 363:6, 581-583
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- Letters
