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`VOL. 363 NO. 6
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`ESTABLISHED IN 1812
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`AUGUST 5, 2010
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`NEJM.0RG
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`THIS WEEK IN THEjOUINAL
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`TheLNEW ENGLAND
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`Health Serials
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`PIISFEC‘I’IVE
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`The “Meaningful Use" Regulation for Electronic
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`D. Blumenthal and M. Tavenner
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`Finding My Way to Electronic Health Records
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`Bracing for the Impact of Expanded Second
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`Private-Party Gun Sales, Regulation, and Public Safety
`6.]. Wintemute. A.A. Braga, and OM. Kennedy
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`ORIGINAL Mucus
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`Nanofiltered C1 Inhibitor Concentrate
`
`for Treatment of Hereditary Angioedema
`B.L. Zuraw and Others
`
`Ecallantide for the Treatment of Acute Attacks
`
`in Hereditary Angioedema
`M. Cicardi and Others
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`Icatibant, a New Bradykinin-Receptor Antagonist,
`in Hereditary Angioedema
`M. Cicardi and Others
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`Suicide-Related Events in Patients Treated
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`with Antiepileptic Drugs
`A. Arana and Others
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`Myocardial Fibrosis as an Early Manifestation
`of Hypertrophic Cardiomyopathy
`C.Y, Ho and Others
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`CLINICAL PRACTICE
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`Transverse Myelitis
`E.M. Frohman and D.M. Wingerchuk
`IMAGES IN CLINICAL MEDICINE
`Velvet Palms
`E.M. Klaus
`
`“Cotton Wool" Appearance of Paget’s Disease
`P. Bhargava andJ.H. Maki
`CLINICAL PIOILEM-SOLVING
`
`Thinking Inside the Box
`P.Jesse| and Others
`EDITORIAL
`
`Hereditary Angioedema — Therapies Old and New
`B.P. Morgan
`HEALTH POLICY anon
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`Health Reform, Primary Care, and Graduate
`Medical Education
`
`J,K. lglehart
`COIIESPONDENCE
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`Radiosurgery for Brain Metastases
`Redesign of Internal-Medicine Teaching
`Helicobacter pylori Infection
`Nonadherence to lmatinib during an Economic
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`Immigrants' Experience with Publicly Funded
`Private Health Insurance
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`Owned & published by the MASSACHUSETTS MEDICAL SOCIETY (9 2010.
`All rights Mmtd. ISSN 00284793.
`
`598
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`S99
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`COIIIC‘I’ION
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`CONTINUING MIDICAL IDUCATIOI
`
`‘ 610.5 NE
`v.363 no.6 Aug.
`
`SSIL-96186
`
`5 2010
`
`8" 3111533
`98 X08 0d
`OS H1183H
`IISHSAINH
`1916001 “
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`
`CSL EXHIBIT 1008
`CSL v. Shire
`
`Page 1 of 11
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`

`

`The NEW ENGLAND
`JOURNAL of MEDICINE
`
`ESTABLI S H E D IN 1 8 12
`
`AUGUSTS, 2010
`
`VOL. 363 NO. 6
`
`Nanofiltered Cl Inhibitor Concentrate for Treatment
`of Hereditary Angioedema
`
`Bruce L. Zuraw, M.D., Paulaj. Busse, M.D., Martha White, M.D.,JoshuaJacobs, M.D., William Lumry, M.D.,
`James Baker, M.D., Timothy Craig, D.O.,J. Andrew Grant, M.D., David Hurewitz, M.D., Leonard Bielory, M.D.,
`William. E. Cartwright, M.D., Majed Koleilat, M.D., Walter Ryan, D.O., Oren Schaefer, M.D., Michael Manning, M.D.,
`Pragnesh Patel, M.D.,Jonathan A. Bernstein, M.D., Roger A. Friedman, M .D., Robert Wilkinson, M.D.,
`David Tanner, M.D., Gary Kohler, M.D., Glenne Gunther, M.D., Robyn Levy, M.D.,James McClellan, M.D.,
`Joseph Redhead, M.D., David Guss, M.D., Eugene Heyman, Ph.D., Brent A. Blumenstein, Ph.D., Ira Kalfus, M.D.,
`and Michael M. Frank, M.D.
`
`in the
`Authors' affiliations are listed
`Appendix. Address reprint requests to
`Dr. Zuraw at 9500 Gilman Dr., Mailcode
`0732, La Jolla , CA 92093-0732, or at
`bzuraw@ucsd.edu.
`
`N Engl J Med 2010;363:513-22.
`Copyright © 2010 Massachusetts Medical Society.
`
`ABSTRACT
`
`BACKGROUND
`Hereditary angioede~a due to Cl 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 Cl inhibitor concen(cid:173)
`trate in the management of hereditary angioedema. The first study compared nano(cid:173)
`filtered Cl inhibitor concentrate with placebo for treatment of an acute attack of
`angioedema. A total of 68 subjects (35 in the Cl 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 Cl inhibitor con(cid:173)
`centrate (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 Cl 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 Cl inhibitor concentrate given as prophylaxis, as compared
`with 12.73 with placebo (P<0.001); the subjects who received the Cl inhibitor concen(cid:173)
`trate 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 Cl inhibitor concentrate short(cid:173)
`ened the duration of acute attacks. When used for prophylaxis, nanofiltered Cl
`inhibitor concentrate reduced the frequency of acute attacks. (Funded by Lev Pharma(cid:173)
`ceuticals; ClinicalTrials.gov numbers, NCT00289211, NCT01005888, NCT00438815,
`and NCT00462709.)
`
`N ENGL) MED 363;6 NEJM .O RG AUGUST 5, 2010
`
`513
`
`Page 2 of 11
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`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`H EREDITARY ANGIOEDEMA DUE TO C1
`
`inhibitor deficiency is an autosomal dom(cid:173)
`inant 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 mucosa! swelling, are
`often associated with severe abdominal pain, nau(cid:173)
`sea, and vomiting. Such attacks frequently lead to
`hospitalization and occasionally to unnecessary
`exploratory surgery. 2 Laryngeal attacks are asso(cid:173)
`ciated 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 lev(cid:173)
`els of Cl inhibitor, whereas type II (15% of cases)
`is characterized by normal antigenic levels of Cl
`inhibitor but low functional levels. 3•4 Both types
`are due to mutations in the Cl inhibitor gene.5•8
`Anabolic androgens and antifibrinolytic drugs
`are used for the prophylactic management of he(cid:173)
`reditary angioedema,9,10 but these agents may be
`associated with clinically significant adverse
`effects.11•12 Cl inhibitor concentrates have been
`shown to be effective in the treatment of acute
`attacks in patients with hereditary angioede(cid:173)
`ma, 1
`9 and their use is supported by the results
`3-1
`of randomized trials1 8 ,19 and by published consen(cid:173)
`sus statements. 20 ,21
`A nanofiltered Cl inhibitor concentrate (Cin(cid:173)
`ryze, ViroPharma) has recently been developed.
`We report the results of two randomized trials
`of nanofiltered Cl 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 spon(cid:173)
`sored by Lev Pharmaceuticals (now owned by
`ViroPharma Biologics). The investigators at each
`of the participating centers conducted the stud(cid:173)
`ies and collected the data with the assistance of
`a contract research organization. Data analysis
`was performed by the investigators with the as(cid:173)
`sistance of consulting statisticians hired by Lev
`~harmaceuticals. The sponsor and its representa(cid:173)
`tives had no role in the study design, data collection
`
`or analysis, or decisions concerning submission of
`the data for publication. All the authors contrib(cid:173)
`uted 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 Clq level, and a low anti(cid:173)
`genic or functional Cl inhibitor level or a muta(cid:173)
`tion in the Cl inhibitor gene known to cause
`hereditary angioedema. Exclusion criteria includ(cid:173)
`ed a low Clq level, a history of a B-cell cancer,
`the presence of anti-Cl inhibitor antibody, a his(cid:173)
`tory of allergic reaction to Cl inhibitor or other
`blood or plasma products, pregnancy, and nar(cid:173)
`cotic addiction. Subjects were not required to
`change any of their regular medications, includ(cid:173)
`ing androgens or antifibrinolytic drugs. All par(cid:173)
`ticipants provided written informed consent.
`
`NANOFILTERED Cl INHIBITOR CONCENTRATE
`The Cl inhibitor concentrate was prepared by
`Sanquin in the Netherlands with the use of plas(cid:173)
`ma obtained in the United States. Briefly, Cl in(cid:173)
`hibitor was purified by a combination of cryo(cid:173)
`precipitation, ion-exchange chromatography, and
`polyethylene glycol precipitation. The resulting
`Cl inhibitor fraction was pasteurized, double(cid:173)
`nanofiltered with the use of 15-nm Planova fil(cid:173)
`ters (Asahi Kasei Medical), and lyophilized.
`
`STUDY DESIGN
`Treatment of Acute Attacks
`For the acute-attack treatment study, eligible sub(cid:173)
`jects were enrolled and then asked to return to the
`study site within 4 hours after the onset of an
`acute attack. (See Fig. lA in the Supplementary
`Appendix, available at NEJM.org.) Study personnel
`were available at all times, and subjects who pre(cid:173)
`sented with an acute attack were assessed on the
`basis of additional criteria to determine whether
`the attack itself qualified for trial eligibility. At(cid:173)
`tacks were excluded if the subject had used nar(cid:173)
`cotics within the previous 7 days or had increased
`the use of anabolic androgens within the previ(cid:173)
`ous 5 days. Attacks of laryngeal angioedema
`were also excluded, and subjects with such at(cid:173)
`tacks were treated with open-label nanofiltered
`
`Page 3 of 11
`
`

`

`Cl INHIBITOR FOR HEREDITARY ANGIOEOEMA
`
`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 pretreat(cid:173)
`ment 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.
`
`Cl inhibitor concentrate. In addition, subjects
`were asked to rate their angioedema symptoms
`as none, mild, moderate, or severe for each af..
`fected site (extremities, throat, abdomen, face,
`and external genitalia). Only subjects with at(cid:173)
`tacks 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 Cl inhibitor concentrate (1000 units in 10 ml
`of sterile water) or placebo (10 ml of saline) ad- Prophylaxis
`ministered by intravenous push over a 10-minute
`In the prophylaxis study, nanofiltered Cl inhibi(cid:173)
`period. Subjects were asked to report the sever-
`tor concentrate was compared with placebo for
`ity of symptoms at each involved site with the preventing attacks of angioedema during a 24-
`use of the following descriptions: absent now week crossover period. Subjects who had been
`and absent before; absent now but present before;
`randomly assigned to a study drug in the acute(cid:173)
`present, symptoms new; present, symptoms worse attack treatment study and who also had a his(cid:173)
`or the same; or present, symptoms better. 17 If tory of at least two attacks per month were eligible
`the subject did not report that symptoms at the
`to participate in the prophylaxis study (Fig. 1B in
`defining site were either absent or better by 60
`the Supplementary Appendix). Subjects were not
`minutes after the initial injection of the study allowed to change their prophylactic androgen or
`drug (Cl inhibitor or placebo), a second injec-
`antifibrinolytic medications during or for 30 days
`tion of the same study drug was administered.
`before the prophylaxis study.
`Symptom severity was assessed every 15 min-
`This study consisted of two consecutive 12-
`utes, beginning with the initial injection and week treatment periods during which subjects
`continuing until the subject reported unequivo-
`received prophylactic injections every 3 to 4 days.
`cal relief at the defining site, with unequivocal Subjects were randomly assigned to receive either
`relief defined as three consecutive reports of im- Cl inhibitor concentrate (1000 units in 10 ml of
`provement at that site. If 4 hours elapsed without sterile water) or placebo (10 ml of saline) during
`unequivocal relief, the assessments were discon-
`the first period. During the second period, they
`tinued, and rescue therapy with open-label Cl received the -study medication that had not been
`inhibitor was offered. Subjects were subsequently assigned during the first period. Subjects were
`contacted by telephone to confirm the complete asked to keep a daily diary of symptoms through(cid:173)
`resolution of symptoms and were asked to return out both study periods. All subjects with acute
`for a follow-up office visit at 3 months. Levels of attacks of angioedema were eligible for rescue
`Cl inhibitor and C4 were measured before the
`treatment with open-label Cl inhibitor. Prophy(cid:173)
`infusion and 60 minutes, 2 hours, and 4 hours
`lactic study injections were delayed for at least 24
`after the infusion.
`hours after open-label rescue treatment for an
`The primary end point was the time from ad-
`acute attack.
`ministration of the study drug to unequivocal re-
`The primary efficacy end point for the prophy(cid:173)
`lief of symptoms at the defining site (i.e., the first
`lactic study was the number of attacks of angio(cid:173)
`of three consecutive reports of improvement). Sec-
`edema during each treatment period, which we
`ondary efficacy end points included the percent- normalized for the number of days the subject
`age of subjects who had an onset of unequivocal participated during that period. We ~id this by
`relief within 4 hours after treatment the time to dividing the total number of attacks m each pe(cid:173)
`complete resolution of the attack (i.~., all symp- , riod by the number ~f days the s~bj~ct partici(cid:173)
`toms of swelling absent), and the effects of treat- pated during that period and multrplymg the re(cid:173)
`ment on antigenic and functional levels of Cl suiting number of attacks per day by 84 (7 x 1~)
`to yield the number of attacks per 12-week peri-
`inhibitor and on C4 levels. Safety was evaluated
`
`N ENGLJ MED 363;6 NEJM .ORG AUGUST 5, 2010
`
`515
`
`Page 4 of 11
`
`

`

`Tht NEW ENGLAND JOURNAL of MEDICINE
`
`od. Secondary end points, reported for each pe(cid:173)
`riod, included the average severity of attacks,
`average duration of attacks, number of open-label
`injections of Cl inhibitor, and total number of
`days of swelling. In addition, changes from
`baseline in antigenic and functional levels of
`Cl inhibitor were evaluated. Safety assessments
`included the extent of exposure; the number and
`severity of adverse events; and changes in clini(cid:173)
`cal 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 ex(cid:173)
`tension trial.
`
`was performed on the basis of a Poisson assump(cid:173)
`tion, with effects for treatment sequence, treat(cid:173)
`ment period, and subjects within sequence; each
`subject served as his or her own control. 23 All sub(cid:173)
`jects 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 con(cid:173)
`sidered to indicate statistical significance. Analy(cid:173)
`ses and summaries were produced with the use
`of SAS software (version 8.2, SAS Institute).
`
`RESULTS
`
`STATISTI CAL AN ALYSI S
`For the acute-attack treatment study, the primary
`outcome variable was the time to the onset of
`unequivocal relie£ The between-group compari(cid:173)
`son was performed by means of a Cox propor(cid:173)
`tional-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 Cl inhibitor administration) within
`4 hours of the study drug injection was consid(cid:173)
`ered a treatment failure as well as a competing
`event, because such rescue interventions preclud(cid:173)
`ed observation of the event of interest. Data for
`subjects who did not have an onset of unequivo(cid:173)
`cal relief of symptoms by 4 hours after treatment
`were censored at 4 hours. The estimated median
`time to the onset of unequivocal relief was calcu(cid:173)
`lated 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 treat(cid:173)
`ment groups by means of the Cochran-Mantel(cid:173)
`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 Cl inhibitor
`minus the attack rate during the administration
`of placebo. A generalized-estimating-equation
`analysis of variance for the crossover study design
`
`AC UTE-ATTAC K T REAT MENT T RIAL
`From March 14, 2005, through May 18, 2007, a
`total of 324 subjects were screened at 37 study
`sites (Fig. lA 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 Cl inhibitor (36 subjects) or placebo (35
`subjects). After completion of the study treat(cid:173)
`ment, 3 subjects (1 in the Cl inhibitor group and
`2 in the placebo group) were judged by an inde(cid:173)
`pendent, blinded expert to have had episodes
`that were not true attacks of angioedema. These
`subjects were therefore excluded from the effi(cid:173)
`cacy analysis. Table 1 shows the baseline charac(cid:173)
`teristics of the remaining 68 subjects.
`The estimated median time to the onset of
`unequivocal relief was 2 hours in the Cl inhibitor
`group, as compared with more than 4 hours in
`the placebo group (estimated success rate ratio,
`2.41; 95% confidence interval [Cl], 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 randomiza(cid:173)
`tion, or defining attack site (Part 2A in the Sup(cid:173)
`plementary Appendix). When the three subjects
`who were judged not to have had true attacks of
`angioedema were included in the primary end(cid:173)
`point analysis, the Cl inhibitor group still had a
`significant benefit with respect to the time to the
`onset of unequivocal relief (estimated success ra(cid:173)
`tio, 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 Cl in(cid:173)
`hibitor group and in 14 of the 33 subjects in the
`placebo group (60% vs. 42%, P=0.06) (Fig. 1).
`
`516
`
`N ENG L J MED 363;6 N EJ M . O RG
`
`AU G U ST 5, 2010
`
`Page 5 of 11
`
`

`

`Cl INHIBITOR FOR HER E DI T ARY A NGIOEDEMA
`
`Table 1. Baseline Characteristics of the Subjects in the Acute-Attack Treatment Trial and the Prophylaxis Trial.*
`
`Characteristic
`
`Acute-Attack Treatment Trial
`
`Prophylaxis Trial
`
`Placebo
`(N=33)
`
`Cl Inhibitor
`(N=35)
`
`Placebo with Crossover
`to Cl Inh ibitor
`(N=ll)
`
`Cl Inhibito r with Crossover
`to Placebo
`(N = ll)
`
`no. (%)
`
`General
`yr
`Age -
`Female sex -
`Weight - kg
`Height -
`cm
`Years since diagnos is
`Type II hereditary angioedema -
`no. (%)t
`Race or ethn ic group -
`White
`Black
`Hispanic
`Site of defining attack- no. (%)
`Abdominal
`External gen italia
`Face
`Androgen therapy at baseline -
`
`no. (%)
`
`no. (%):j:
`
`36.2±13.8
`27 (81.8)
`77.4±22.6
`167.8±10.4
`20.5±18.8
`6 (18.2)
`
`36.7±17.9
`26 (74.3)
`80.9±28.3
`163.1±14.1
`18.4±11.6
`6 (17.1)
`
`30 (90.9)
`1 (3.0)
`2 (6.1)
`
`26 (78.8)
`2 (6.1)
`5 (15 .2)
`11 (33 .3)
`
`33 (94.3)
`1 (2.9)
`1 (2.9)
`
`24 (68.6)
`7 (20.0)
`4 (11.4)
`16 (45.7)
`
`34.5±14.8
`11 (100)
`76.3±25.7
`163.2±8.8
`16.8±7.9
`2 (18.2)
`
`11 (100)
`0
`0
`
`41.7±19.3
`9 (81.8)
`70.5±9.3
`166.2±6.9
`19.3±14.4
`2 (18.2)
`
`10 (90.9)
`1 (9.1)
`0
`
`1 (9.1)
`
`2 (18.2)
`
`* Plus- minus values are means ±SD. Differences between treatment groups were not significant.
`t Race or ethnic group was self-reported .
`:j: Androgen therapy in the prophylaxis trial consisted of oxandrolone in different doses.
`
`A second dose of the blinded study drug was
`administered to 23 subjects in the Cl inhibitor
`group and to 28 patients in the placebo group
`(Part 2B in the Supplementary Appendix). The
`median time to complete resolution of symp(cid:173)
`toms was 12.3 hours in the Cl inhibitor group
`and 25.0 hours in the placebo group (P=0.004),
`even though all subjects who did not have sub(cid:173)
`stantial improvement by the end of the 4-hour
`assessment period were given open-label Cl in(cid:173)
`hibitor. Both antigenic and functional levels of
`Cl inhibitor increased significantly during treat(cid:173)
`ment in the group given Cl inhibitor but not in
`the group given placebo (P<0.001 for both be(cid:173)
`tween-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 ran(cid:173)
`domly assigned to one of two groups: 12 to pla(cid:173)
`cebo and 12 to Cl 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 peri(cid:173)
`od and then crossed over to the other study treat(cid:173)
`ment 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 Cl inhibitor
`and placebo treatments, respectively (Fig. 2). The
`estimated average difference in attack rates be(cid:173)
`tween subjects receiving Cl 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 at(cid:173)
`tacks (on a 3-point scale, with 1 indicating mild,
`2 moderate, and 3 severe) was significantly lower
`with Cl inhibitor prophylaxis than with placebo
`(1.3±0.85 vs. 1.9±0.36, P<0.001) (Fig. 3). Likewise,
`the total duration of attacks was significantly
`shorter with Cl inhibitor prophylaxis than with
`
`N EN G LJ M ED 363;6 NEJM .O RG AUG U ST 5, 2010
`
`517
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`Page 6 of 11
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`

`

`Tht NEW ENGLAND JOURNAL of MEDICINE
`
`25
`
`Cl inhibitor (21 subjects reported relie~
`
`~ z
`
`20
`
`15
`
`cl
`.s
`~
`..
`0::
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`-g 10
`
`100
`
`80
`
`60
`
`l
`I 40
`
`:,
`VI
`
`20
`
`120
`180
`60
`Time after First Dose (min)
`
`240
`
`0
`
`Placebo
`
`Cl Inhibitor
`
`Figure 1. Primary Outcome in the Trial of Cl Inhibitor
`Therapy for Acute Attacks of Angioedema.
`Cumulative incidence estimates for the time to the on(cid:173)
`set of unequivocal relief (primary outcome) are shown
`for 35 subjects who received nanofiltered Cl inhibitor
`concentrate and 33 subjects who rece ived placebo. The
`circles represent either subjects who received rescue
`therapy before 4 hours (competing events; 2 subjects
`in the placebo group received narcotic rescue at 15 and
`146 minutes, respectively, and 1 subject in the Cl inhib(cid:173)
`itor group received open-label Cl inhibitor rescue at
`110 minutes) or those who did not have an onset of
`unequivocal relief before 4 hours.
`
`placebo (2.1±1.13 vs. 3.4±1.39 days, P=0.002). A
`total of 11 subjects receiving Cl inhibitor pro(cid:173)
`phylaxis required open-label rescue therapy, as
`compared with 22 subjects receiving placebo. Cl
`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 re(cid:173)
`ceived open-label Cl inhibitor treatment for a total
`of 447 separate attacks, with the number of at(cid:173)
`tacks 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(cid:173)
`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 Cl inhibitor
`
`Figure 2. Normalized Rate of Angioedema Attacks
`during the Prophylaxis Trial.
`The attack rates are shown for each of the 22 subjects
`during the 12-week period when either placebo or nano(cid:173)
`filtered Cl inhibitor was being administered . Each pair
`of connected points represents the attack rates for a
`single subject during the two periods. The black hori(cid:173)
`zontal lines indicate mean attack rates for the two treat(cid:173)
`ments , wh ich were 6.3 and 12.7 for the Cl inhibitor
`group and the placebo group, respectively.
`
`(17%) and 7 of the 35 subjects randomly assigned
`to placebo (20%) had adverse events (Table 2).
`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 Cl inhibi(cid:173)
`tor 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 Cl inhibitor replacement therapy for
`the treatment of acute attacks in subjects with he(cid:173)
`reditary angioedema was first reported 30 years
`ago. 16 A number of subsequent studies have also
`shown a beneficial effect of such therapy,1 Hs in(cid:173)
`cluding two placebo-controlled trials. 18•19 In
`countries where Cl inhibitor replacement therapy
`is available, consensus statements affirm its use
`as the standard of care for acute attacks of heredi(cid:173)
`tary angioedema. 20,21
`In our acute-attack treatment trial, nanofil(cid:173)
`tered Cl inhibitor concentrate significantly reduced
`the time to the onset of unequivocal relief of
`symptoms as compared with placebo. However,
`
`518
`
`N EN G L) M EO 363;6 NEJM . O RG AUG U ST 5, 2010
`
`Page 7 of 11
`
`

`

`Cl INHIBITOR FOR HEREDITARY ANGJO E DEMA
`
`Subject
`No.
`
`Placebo
`
`Subject
`No.
`
`Cl Inhibitor
`
`2 -.... ...... - . ...................... _
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`, L , ,
`13 , I , , , , I , I , , , , 1 ,
`, ... ,
`,
`14 .......... _
`........ _ __ _ __ _ ...... __
`
`15 .
`
`.. , ~ , , , , I , , , , , , , , ... .. ., • • •
`" t " N
`" I, t t t "
`I
`16
`1 1
`17
`• 1
`..
`18, , , , , JI , , , , , , , , , , , 11
`19 I
`I ala
`20 ............. +..iil-------+1 ....... 4 .................. ........ 4 ....... ........
`21 -· -· -~-l11-o, ..... , ..... ,_, .......................... ~ -· -·-·-·-·_. . .. .
`22 _
`................................................ _.. ..... ,..._ ..... ........
`
`•
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`• •
`
`,
`
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`
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`
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`
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`
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`
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`
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`
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`
`0
`
`20
`
`40
`60
`Day within Period
`
`80
`
`100
`
`0
`
`20
`
`40
`60
`Day within Period
`
`80
`
`100
`
`Figure 3. Major Events during the Prophylaxis Trial.
`Each of the 22 subjects received prophylactic injections (black circles) of either placebo or nanofiltered Cl inhibitor
`concentrate for 12 weeks each in crossover fashion . The orange bars represent the daily angioedema scores, with
`bar heights correlating with mild, moderate, or severe attacks. The blue bars indicate open-label rescue treatments
`with Cl inhibitor concentrate (shorter bars, 1000-unit dose; taller bars, 2000-unit dose). Three subjects were also
`receiving attenuated androgen therapy at baseline: Subject 13 (oxandrolone, 2.5 mg per day), Subject 16 (oxandro·
`lone, 2.5 mg every other day) , and Subject 17 (oxandrolone, 10 mg per day) .
`
`40% of subjects treated with Cl 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, 1 8 ,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 Cl 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 Cl inhibitor concentrate for treat(cid:173)
`ment of acute attacks. In this analysis, symptoms
`improved within 4 hours in 93% of 447 treat(cid:173)
`ments. The efficacy of Cl inhibitor for the treat(cid:173)
`ment 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 in(cid:173)
`vestigators. 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 prophylac(cid:173)
`tic treatment. Short-term prophylaxis is routinely
`given before dental procedures or other situa(cid:173)
`tions likely to precipitate an acute attack, and Cl
`inhibitor replacement, in the form of either
`fresh-frozen plasma or Cl inhibitor concentrate,
`has been shown to be effective for this pur(cid:173)
`pose. 25 •26 There are also anecdotal reports of Cl
`inhibitor concentrate being given intravenously
`for long-term prophylaxis.15 •27•28 In a crossover
`study, Waytes et al. found that prophylactic treat(cid:173)
`ment with vapor-heated Cl 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 tri(cid:173)
`al, nanofiltered Cl inhibitor concentrate signifi(cid:173)
`cantly reduced the fre