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

Article (PDF Available)inThe Journal of allergy and clinical immunology 124(4):801-8 · September 2009with30 Reads
DOI: 10.1016/j.jaci.2009.07.017 · Source: PubMed
Abstract
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.
Efficacy of human C1 esterase inhibitor concentrate
compared with placebo in acute hereditary angioedema
attacks
Timothy J. Craig, MD,
a
Robyn J. Levy, MD,
b
Richard L. Wasserman, PhD, MD,
c
Againdra K. Bewtra, MD,
d
David Hurewitz, MD,
e
Krystyna Obtu1owicz, MD,
f
Avner Reshef, MD,
g
Bruce Ritchie, MD,
h
Dumitru Moldovan, MD,
i
Todor Shirov, MD,
j
Vesna Grivcheva-Panovska, MD,
k
Peter C. Kiessling, PhD,
l
Heinz-Otto Keinecke, MS,
m
and Jonathan A. Bernstein, MD
n
Hershey, Pa, Atlanta, Ga, Dallas, Tex, Omaha, Neb, Tulsa, Okla, Krakow, Poland, Tel Hashomer, Israel,
Edmonton, Alberta, Canada, Tirgu Mures, Romania, Sofia, Bulgaria, Skopje, Republic of Macedonia, Marburg, Germany, and Cincinnati, Ohio
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 5 .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 5 .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. (J
Allergy Clin Immunol nnnn;nnn:nnn-nnn.)
Key words: C1 inhibitor, C1-INH, C1 inhibitor deficiency, angioe-
dema, hereditary angioedema, HAE
Hereditary angioedema (HAE) is a rare disorder with 3 known
forms (types I, II, and III). Whereas types I and II are characterized
by quantitative and/or functional C1 esterase inhibitor (C1-INH)
deficiency, type III is characterized by normal complement lev els
and may be caused by mutations in the factor XII gene.
1,2
C1-INH is
one of the control proteins that regulates vascular permeability for
the complement system.
3-5
By inhibiting components of the comple-
ment (specifically C1r and C1s), contact (factor XII and kallikrein),
coagulation (factor XI and thrombin), and brinolytic (tissue-type
plasminogen activator and brinolysin) systems, C1-INH regulates
the generation of vasoactive peptides, of which bradykinin is consid-
ered the most important.
3,6,7
The regulation of bradykinin is a key
step in preventing the development of angioedema.
8,9
In type I
HAE, impaired synthesis of functionally activ e C1-INH and
elevated turnover result in insufcient plasma concentrations of
C1-INH, whereas in type II HAE, a dysfunctionalC1-INH molecule
is synthesized in normal amounts.
10
Except for 1 homozygous fam-
ily,
11
both defects are inherited as an autosomal-dominant trait.
12
The clinical manifestations of type I or II HAE are episodic bouts
of well circumscribed, non-itching swelling of the deep cutaneous,
subcutaneous, submucosal, and subepithelial tissues.
12,13
Patients
may experience swelling of the abdomen, face, genitalia, and ex-
tremities, abdominal pain, nausea, vomiting, or diarrhea, as well
as life-threatening swelling of the larynx.
14
Therapeutic options that are effective for histamine-induced
angioedema,such as corticosteroids, antihistamines,orepinephrine,
From
a
the Penn State University College of Medicine;
b
the Family Allergy and Asthma
Center, Atlanta;
c
DallasAllergyImmunology;
d
the Creighton University School of
Medicine, Omaha;
e
the Allergy Clinic of Tulsa, Inc;
f
Jagiellonian University Hospital,
Krakow;
g
the Chaim Sheba Medical Center, Tel Hashomer;
h
the Departments of Med-
icine and Medical Oncology, University of Alberta;
i
the 4th Medical Clinic, University
of Medicine and Pharmacy, Tirgu Mures;
J
the Tsarita Yoanna Hospital, Ear, Nose, and
Throat Clinic, Sofia;
k
the PHI-University Clinical Center, Department of Dermatol-
ogy, Allergology and Clinical Immunology, Skopje;
l
CSL Behring GmbH, Marburg;
m
Accovion GmbH, Marburg; and
n
the University of Cincinnati Medical Center and
Bernstein Clinical Research Center.
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 Al-
lergy, 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 re-
search support from CSL Behring, Pfizer, Merck, and the National Institutes of Health.
D. Hu rewitz has served as a consultant for CSL Behring and has received research sup-
port 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 Cana-
dian Immunodeficiency Patient Organization, Medical and Scientific Advisory Com-
mittees. 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.
Received for publication January 22, 2009; revised July 7, 2009; accepted for publication
July 14, 2009.
Available online September xx, 2009.
Reprint requests: Peter C. Kiessling, PhD , CSL Behring GmbH, Clinical Research and
Development, Emil-von-Behring-Str 76, 35041 Marburg, Germany. E-mail: peter.
kiessling@cslbehring.com.
0091-6749/$36.00
Ó 2009 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2009.07.017
1
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Abbreviations used
C1-INH: C1 esterase inhibitor
HAE: Hereditary angioedema
have no effect on the pathophysiology of an acute HAE attack.
6,15
Current treatment options in the United States for an acute type I
or II HAE attack include fresh frozen plasma and e-amino-caproic
acid, which have variable efficacy and are associated with signif-
icant side effects.
16
Outside the United States, the treatment of
choice for an acute type I or II HAE attack is rapid replacement
of the missing functional plasma protein C1-INH.
17-19
Berinert (CSL Behring, Marburg, Germany) is a highly puri-
fied, virus-inactivated C1-INH concentrate
20
that is derived
from human plasma collected in the United States. It is approved
for the treatment of acute HAE attacks in several European and
South American countries as well as in Japan; altogether, more
than 400,000 treatments have been administered in more than
30 years of use. Approval is currently being sought for marketing
in the United States (orphan drug designation).
To date, there is insufficient information from placebo-controlled
studies to establish the effecti v e dose of C1-INH concentrate in the
treatment of acu te HAE attacks. C1-INH was reported as being
eff ective in the treatment of acute attacks in an earlier and smaller
double-blind, placebo-controlled study with doses of 23 to 39 U/kg,
21
and in an earlier uncontrolled study (not published) with doses equiv-
alent to 6 to 15 U/kg body weight. Thus, we designed the current
study (I.M.P.A.C.T.1) to assess the efficacy and safety of C1-INH
(Berinert) at a dose of 20 U/kg, compared with placebo. A secondary
objective was to ev aluate the efficacy of a lower dose of 10 U/kg.
METHODS
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 approved the protocol, and written informed consent was
obtained from each patient or, in the case of a minor, from a legally acceptable
representative. An independent data and safety monitoring board oversaw the
safety of the study.
Patients were eligible if they were at least 6 years of age and had laboratory-
confirmed C1-INH deficiency (type I or II HAE) and were then treated on
presentation of an acute moderate to severe abdominal or facial attack within 5
hours of the attack attaining moderate intensity (as assessed by the patient and
confirmed by the investigator).
Relevant exclusion criteria included history of hypersensitivity to C1-INH
concentrates, acquired angioedema, all other types of angioedema and
abdominal pain not associated with C1-INH deficiency, habitual use of
narcotics or use of pain medication during a current attack, and treatment with
any C1-INH concentrate or other drug appropriate for acute angioedema, or
with fresh frozen or native plasma, within 7 days before the start of treatment.
Randomization was performed by using a centralized, validated comput-
erized system that assigned a unique patient number to each participant.
For each patient, only a single abdominal attack (gastrointestinal colic, not
cutaneous) or facial attack (not laryngeal) was treated and evaluated. Patients
received a single intravenous infusion of either C1-INH (Berinert) at a dose of
10 or 20 U/kg, or placebo. In addition to the usual precautions, the double-
blinding was considered to have been maintained because the volume and
appearance of all 3 treatments were identical, and there were no dose-related
local or systemic reactions associated with the treatments.
Patients were observed for a minimum of 4 hours after the start of
treatment, after which they could be discharged from the center if they had
reported onset of symptom relief. After 4 hours, patients who reported
insufficient or no symptom relief could receive a second dose of double-blind
treatment (called ‘rescue study medication’’) as follows: C1-INH 20 U/kg for
patients on placebo, C1-INH 10 U/kg for patients on C1-INH 10 U/kg, and
placebo for patients on C1-INH 20 U/kg. A viral safety assessment was
performed before and for as long as 12 weeks after treatment.
Study outcomes
The primary endpoint was the time from the start of treatment to the onset
of symptom relief, as determined by patient responses to a standard question
posed at appropriate time intervals for as long as 24 hours after the start of
treatment. To provide a stringent analysis, the time to onset of symptom relief
was set at 24 hours if a patient received rescue study medication before the
onset of relief, or received analgesics, antiemetics, or open-label C1-INH or
fresh frozen plasma during the first 4 hours after treatment.
This type of endpoint has been widely reported in the scientific literature for
the evaluation of HAE therapies (eg, Waytes et al,
17
Kunschak et al,
21
and sub-
sequent studies summarized by Frank
22
) and is also accepted by regulators in
the United States and Europe.
23,24
In addition, we retrospectively validated the
primary endpoint by correlation with the course of the associated HAE symp-
toms (data on file). Secondary endpoints were the time to complete resolution
of all HAE symptoms, the proportion of patients with worsened intensity of
HAE symptoms between 2 and 4 hours after the start of treatment compared
with baseline for at least 1 HAE symptom present at baseline, and the number
of vomiting episodes within 4 hours after the start of treatment.
Other data captured included adverse events occurring as long as 9 days after
treatment (serious adverse events as long as 12 weeks after treatment), vital
signs (blood pressure, heart and respiratory rate, body temperature) before and
as long as 24 hours after treatment, and viral safety (HIV types 1 and 2, hepatitis
virus, and human B19 virus) before and as long as 12 weeks after treatment.
Statistical analysis
The planned sample size was 42 patients per treatment group, which was
the maximum feasible number in this rare disease. Efficacy analyses were
based on the intention-to-treat principle and included all patients who received
any blind study treatment. The patients were analyzed according to the
treatment group to which they were randomized.
The primary variable, time to onset of symptom relief for C1-INH 20 U/kg
versus placebo, was evaluated using a Wilcoxon 1-sided, 2-sample test. A
confirmatory test was used for the primary analysis with a maximum allowed
type I error of 0.025, 1-sided, in a group sequential design with a nominal a at
final analysis of 0.024. Because there were only 2 groups, no a correction for
multiple testing was necessary; instead, only a small a correction for
sequential testing was needed. For the secondary objective of dose-finding,
a 2-step closed testing procedure with Wilcoxon 2-sample tests was used with
a maximum allowed type I error of 0.05, 1-sided.
25,26
The secondary efficacy variables of number of vomiting episodes and time
to complete resolution of symptoms were also evaluated by using the
Wilcoxon 1-sided 2-sample test. A 1-sided Fisher exact test was used for
the secondary efficacy variable of worsened intensity of symptoms between 2
and 4 hours after the start of treatment. For all secondary efficacy variables
(except time to complete resolution of all symptoms, which was considered an
exploratory variable), confirmatory tests with a maximum allowed type I error
of 0.1, 1-sided, were carried out. In addition, we conducted efficacy analyses
with a stratified nonparametric Brunner test
27
to investigate the onset of symp-
tom relief stratified by type and intensity of baseline attack.
Safety data were analyzed for all patients who had received any treatment,
according to the actual treatment received. An analysis of adverse events
occurring within 4 hours after treatment was conducted to allow an unbiased
comparison of C1-INH 20 U/kg versus placebo during maximum exposure to
treatment in the acute phase of the attack (ie, without the confounding effect of
any rescue medication). In addition, adverse events were analyzed for all
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2 CRAIG ET AL
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patients who received any C1-INH at any time during the study, including
patients in the placebo group who received C1-INH as rescue medication.
Incidence rates were calculated by system organ class, preferred term, and
dose group. No routine laboratory data were obtained. Vital signs and viral
safety data were analyzed descriptively.
The sponsor’s clinical research department was responsible for designing
and conducting the study, approving the statistical plan, and gathering and
reporting the data. The statistical analyses were conducted by Accovion
GmbH, Marburg, Germany, which vouches for the data and the analysis. The
results of the study were interpreted and discussed by the named authors at a
series of scientific meetings during the development of this article. The
sponsor (represented by P. C. Kiessling) took the lead in writing this article and
coordinated writing of the article with the named authors; the sponsor also
engaged a consultant medical writer to assist with preparation of the first draft
in cooperation with the named authors. The sponsor placed no restrictions on
any of the authors regarding statements made in the article.
RESULTS
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. Over-
all, 98 (79.0%) patients experienced abdominal attacks, and 25
(20.2%) experienced facial attacks. One randomized patient
was excluded from the intention-to-treat population because of
the need for open-label rescue medication before receiving the
randomized treatment (Fig 1).
The percentage of patients who received rescue study medica-
tion was considerably higher with placebo (57.1%) than with
C1-INH 10 U/kg (33.3%) or 20 U/kg (18.6%).
Efficacy outcomes
For the primary efcacy analysis, the time to onset of symptom
relief was set to 24 hours if the patient received rescue study
medication or analgesics, antiemetics, open-label C1-INH, or fresh
frozen plasma after 4 hours. The numbers of patients with values
FIG 1. Patient disposition by treatment group.
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set to 24 hours were 17 of 42 (40.5%) for placebo, 11 of 39 (28.2%)
for C1-INH 10 U/kg, and 6 of 43 (14.0%) for C1-INH 20 U/kg. In
this stringent analysis, the median time to onset of symptom relief
was significantly shorter with C1-INH 20 U/kg (0.5 hours) than
with placebo (1.5 hours; P 5 .0025; Table II). With C1-INH 10 U/
kg, the median time to onset of symptom relief was only slightly
shorter than with placebo (1.2 hours vs 1.5 hours). One hour after
treatment, more than 75% of patients treated with C1-INH 20 U/kg
had reported onset of symptom relief, compared with approxi-
mately 40% of patients treated with placebo (Fig 2, A). Using a
closed testing procedure for dose finding, the comparison of time
to onset of symptom relief revealed statistical significance for
C1-INH 20 U/kg versus 10 U/kg (P 5 .0048), and no statistical sig-
nificance for C1-INH 10 U/kg versus placebo (P 5 .2731).
The median time to onset of symptom relief was relatively short
for abdominal attacks (placebo, 1.3 hours; C1-INH 10 U/kg, 1.2
hours; C1-INH 20 U/kg, 0.5 hours) compared with facial attacks
(placebo, 24.0 hours; C1-INH 10 U/kg, 1.3 hours; C1-INH 20 U/
kg, 0.9 hours; Table III). However, the stratified analysis could not
confirm any difference in treatment effect between facial and ab-
dominal attacks (data not shown). The treatment effect was de-
scribed as an estimated probability in terms of the time to onset
of symptom relief for a patient receiving C1-INH 20 U/kg being
shorter than the respective time for a patient receiving placebo.
TABLE I. Demographic and baseline characteristics (intention-to-treat population)
Characteristic Placebo (N 5 42) C1-INH 10 U/kg (N 5 39) C1-INH 20 U/kg (N 5 43) Overall (N 5 124)
Sex, n (%)
Female 28 (66.7) 26 (66.7) 30 (69.8) 84 (67.7)
Male 14 (33.3) 13 (33.3) 13 (30.2) 40 (32.3)
Age (y)
Mean (SD) 31.5 (13.57) 33.1 (12.77) 34.6 (14.91) 33.1 (13.76)
Range 6-62 13-72 10-71 6-72
Race or ethnic group, n (%)
White 37 (88.1) 36 (92.3) 38 (88.4) 111 (89.5)
Black 1 (2.4) 0 3 (7.0) 4 (3.2)
Hispanic 1 (2.4) 2 (5.1) 2 (4.7) 5 (4.0)
Asian 2 (4.8) 1 (2.6) 0 3 (2.4)
American Indian or Alaskan Native 1 (2.4) 0 0 1 (0.8)
BMI (kg/m
2
)
Mean (SD) 25.3 (6.00) 26.7 (5.29) 27.0 (5.57) 26.4 (5.64)
Range 13-38 17-36 18-40 13-40
Primary disease characteristic, n (%)
Type I HAE 38 (90.5) 35 (89.7) 35 (81.4) 108 (87.1)
Type II HAE 4 (9.5) 3 (7.7) 8 (18.6) 15 (12.1)
Missing 1 (2.6) 1 (0.8)
Intensity of baseline HAE attack, n (%)
Moderate 26 (61.9) 32 (82.1) 27 (62.8) 85 (68.5)
Severe 16 (38.1) 7 (17.9) 16 (37.2) 39 (31.5)
BMI, Body mass index.
TABLE II. Results of primary and secondary efficacy analyses (intention-to-treat population)
Statistic Placebo (N 5 42) C1-INH 10 U/kg (N 5 39) C1-INH 20 U/kg (N 5 43)
P value 20 U/kg
placebo
Time to onset of symptom relief (h), primary efficacy analysis*
Mean (SD) 10.27 (11.481) 7.47 (10.513) 3.89 (8.202)
Median (range) 1.50 (0.20-24.00) 1.17 (0.17-24.00) 0.50 (0.17-24.00) .0025(.0078à)
Time to complete resolution of all HAE symptoms, including pain (h)§
Mean (SD) 125.08 (382.815) 216.06 (494.230) 81.84 (314.347)
Median (range) 7.79 (0.33-1486.17) 20.00 (0.47-1486.17) 4.92 (0.47-1486.17) .0237k
Proportion of patients with worsened intensity of HAE symptoms between 2 and 4 hours after start of treatment
N (%) 13 (31.0) 8 (20.5) 2 (4.7) .0014{
No. of vomiting episodes within 4 hours after start of treatment
Mean (SD) 0.8 (2.59) 0.2 (0.77) 0.1 (0.41)
Median (range) 0 (0-16) 0 (0-4) 0 (0-2) .0329
*Time to onset of symptom relief was set to 24 hours if the patient received rescue study medication or analgesics, antiemetics, open-label C1-INH, or fresh frozen plasma after 4
hours. The numbers of patients with values set to 24 hours were as follows: placebo, 17/42 (40.5%); C1-INH 10 U/kg, 11/39 (28.2%,); C1-INH 20 U/kg, 6/43 (14.0%).
One-sided 2-sample Wilcoxon test.
àExploratory 2-sided log-rank test.
§Irrespective of use of rescue study medication or analgesics, antiemetics, open-label C1-INH, or fresh frozen plasma before onset of symptom relief. Missing values were set to
maximum time to complete resolution (ie, 1486 hours).
kExploratory 1-sided 2-sample Wilcoxon test.
{One-sided Fisher exact test.
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Although the median time to onset of symptom relief was more
pronounced for severe attacks (placebo, 13.5 hours; C1-INH 20
U/kg, 0.5 hours) than for moderate attacks (placebo, 1.3 hours;
C1-INH 20 U/kg, 0.8 hours; Table III), a 2-sided test for interac-
tion could not confirm any difference in treatment effect between
moderate and severe attacks (P 5 .463). In both cases, the efficacy
compared with placebo was greater with C1-INH 20 U/kg than
with C1-INH 10 U/kg.
The results of the secondary efficacy analyses generally
supported the results of the primary analysis (Table II). The me-
dian time to complete resolution of HAE symptoms was signifi-
cantly lower with C1-INH 20 U/kg (4.9 hours) than with
placebo (7.8 hours; P 5 .0237). Compared with placebo, the me-
dian time to complete resolution of HAE symptoms was longer
for the 10 U/kg group, which can be attributed to the confounding
effect of rescue study medication.
The proportion of patients with worsened intensity of HAE
symptoms between 2 and 4 hours after the start of treatment for at
least 1 of the HAE symptoms present at baseline was also
significantly lower with C1-INH 20 U/kg (4.7%) than with
placebo (31.0%; P 5 .0014). The mean number of vomiting epi-
sodes within the first 4 hours after treatment was also significantly
lower with C1-INH 20 U/kg (0.1) than with placebo (0.8; P 5
.0329).
The treatment effect with C1-INH 10 U/kg was less than with
C1-INH 20 U/kg, but greater than with placebo, for the primary
efficacy analysis as well as for the secondary efficacy analyses of
the proportion of patients with worsened intensity of clinical
symptoms and number of vomiting episodes (Table II).
In patients with abdominal or facial attacks treated with C1-
INH 20 U/kg, no new attacks occurred before the complete
resolution of the previous attack, indicating an absence of
rebound angioedema. One patient in this group had a missing
value for the time to complete resolution of 1 attack, but the next
attack in this patient occurred 7 days later. Because the median
elimination half-life of C1-INH is approximately 35 hours,
28
this
subsequent attack cannot reflect any ineffective treatment of the
earlier attack.
FIG 2. Kaplan-Meier curves for time to onset of symptom relief, as determined by patient assessment
(intention-to-treat population). A, Values set to 24 hours if rescue medication was given before onset of
symptom relief (primary analysis). Only the curves for as long as 4 hours after treatment are shown because
values did not change thereafter through 24 hours after treatment. B, Actual values recorded (ie, values not
set to 24 hours if rescue medication was given before onset of symptom relief). BW, Body weight.
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Safety and tolerability
A total of 126 patients (placebo, 41 patients; C1-INH 10 U/kg,
39 patients; C1-INH 20 U/kg, 46 patients) were included in the
safety population (Fig 1).
The percentage of patients experiencing an adverse event
within 4 hours after start of treatment was considerably lower
with C1-INH 20 U/kg (19.6%) than with placebo (43.9%;
Table IV). Adverse events considered at least possibly related
to treatment were also less frequent with C1-INH 20 U/kg
(10.9%) than with placebo (19.5%). Most patients reported
events in the system organ classes of gastrointestinal disorders,
general disorders and administration site conditions, and mus-
culoskeletal and connective tissue disorders, with lower per-
centages among patients treated with C1-INH 20 U/kg than
with placebo for all these categories. The difference between
C1-INH 20 U/kg and placebo was particularly pronounced for
gastrointestinal disorders (10.9% vs 31.7%), which was ex-
pected because most patients experienced abdominal HAE at-
tacks. The most frequent events were nausea, diarrhea,
abdominal pain, and muscle spasms, and the frequencies of
all these events were lower with C1-INH 20 U/kg than with
placebo. Most of these symptoms are related to the underlying
TABLE III. Analyses of time to onset of symptom relief by HAE attack characteristics (intention-to-treat population)
Time to onset of symptom relief (h)*
Characteristic Statistic Placebo (N 5 42) C1-INH 10 U/kg (N 5 39) C1-INH 20 U/kg (N 5 43)
Type of attack
Abdominal N 33 31 34
Mean (SD) 8.59 (11.083) 7.59 (10.680) 3.37 (7.659)
Median (range) 1.25 (0.20-24.00) 1.17 (0.17-24.00) 0.50 (0.17-24.00)
Facial N 8 8 9
Mean (SD) 15.47 (11.802) 7.02 (10.531) 5.89 (10.274)
Median (range) 24.00 (0.25-24.00) 1.32 (0.50-24.00) 0.92 (0.25-24.00)
Intensity of attackà
Moderate N 26 32 27
Mean (SD) 8.92 (11.204) 8.12 (10.885) 4.95 (9.259)
Median (range) 1.33 (0.25-24.00) 1.13 (0.22-24.00) 0.78 (0.17-24.00)
Severe N 16 7 16
Mean (SD) 12.44 (11.953) 4.50 (8.682) 2.11 (5.862)
Median (range) 13.50 (0.20-24.00) 1.35 (0.17-24.00) 0.50 (0.17-24.00)
*Time to onset of symptom relief was set to 24 hours if the patient received rescue study medication or analgesics, antiemetics, open-label C1-INH, or fresh frozen plasma after
4 hours.
One patient was originally randomized with a facial attack, which was later reassessed as a laryngeal attack.
àAssessment of intensity of symptoms of the HAE attack: the intensity (mild, moderate, or severe) was stated by the patient and confirmed by the investigator. Only patients with
moderate to severe HAE attacks were to be included in the study.
TABLE IV. Incidence of adverse events (safety population)
No. (%) of patients
As long as 4 hours after treatment Any time
Adverse event category Placebo (N 5 41) C1-INH 10 U/kg (N 5 39) C1-INH 20 U/kg (N 5 46) C1-INH All doses* (N 5 108)
Patients with adverse events 18 (43.9) 10 (25.6) 9 (19.6) 55 (50.9)
Patients with at least possibly related adverse
events
8 (19.5) 8 (20.5) 5 (10.9) 29 (26.9)
Patients with serious adverse events 0 0 0 4 (3.7)
Patients with adverse events leading to
discontinuation of treatment
00 0 0
Most common adverse events (>1 patient overall)
Hereditary angioedema 0 0 0 14 (13.0)
Headache 2 (4.9) 1 (2.6) 0 13 (12.0)
Abdominal pain 3 (7.3) 1 (2.6) 2 (4.3) 7 (6.5)
Nausea 5 (12.2) 1 (2.6) 3 (6.5) 7 (6.5)
Muscle spasms 2 (4.9) 4 (10.3) 1 (2.2) 6 (5.6)
Pain 1 (2.4) 4 (10.3) 1 (2.2) 6 (5.6)
Diarrhea 4 (9.8) 1 (2.6) 0 5 (4.6)
Vomiting 3 (7.3) 1 (2.6) 1 (2.2) 5 (4.6)
Back pain 1 (2.4) 0 0 4 (3.7)
Dysgeusia 0 1 (2.6) 2 (4.3) 4 (3.7)
Edema peripheral 0 1 (2.6) 1 (2.2) 4 (3.7)
Abdominal distension 0 1 (2.6) 0 2 (1.9)
Upper respiratory tract infection 0 0 0 2 (1.9)
Face edema 1 (2.4) 1 (2.6) 0 1 (0.9)
Lip swelling 1 (2.4) 1 (2.6) 0 1 (0.9)
*Patients treated with C1-INH at any time during the study, including use of C1-INH as rescue medication in the placebo and C1-INH 10 U/kg groups.
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6 CRAIG ET AL
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disease and type of attack. With C1-INH 10 U/kg, the percent-
age of patients with an adverse event (25.6%) was also consid-
erably lower than with placebo (43.9%).
No serious adverse events or adverse events leading to discon-
tinuation of treatment occurred within 4 hours after study
treatment. Later in the study, 4 patients had 9 serious adverse
events of HAE exacerbation. One of these events was considered
at least possibly related to treatment, and this event occurred in
the 1 patient whose diagnosis of HAE was questioned after
genetic testing. The vital signs measurements revealed no signals
of concern.
Virus safety
No seroconversions were observed for HIV, hepatitis virus, or
human B19 virus.
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.
29-34
None of these studies had a randomized, placebo-controlled de-
sign to evaluate the most suitable dose of C1-INH. To address
this issue, we conducted a double-blind, placebo-controlled study
in patients with type I and II HAE, in which single acute HAE at-
tacks were treated with C1-INH 10 or 20 U/kg, or placebo. The
findings demonstrated consistent and statistically significant effi-
cacy of C1-INH 20 U/kg compared with placebo across all effi-
cacy endpoints.
The primary efficacy analysis demonstrated that C1-INH 20 U/
kg provides fast onset of symptom relief within 30 minutes, with a
significant reduction in time to onset of relief compared with
placebo (P 5 .0025). In terms of dose-finding, the comparison of
time to onset of relief revealed statistical significance for C1-INH
20 U/kg versus 10 U/kg (P 5 .0048) and no statistical significance
for C1-INH 10 U/kg versus placebo (P 5 .2731).
No difference in treatment effect in terms of time to onset
of symp tom relief could be confirmed by stratified analysis
when comparing the efficacy of C1-INH 20 U/kg in facial and
abdominal attacks, and in moderate and severe attacks.
Therefore, C1-I NH 20 U/kg may be considered efficacious
irrespective of the body loca tion studied (facial or a bdominal
sites) or the sever ity of an attack. This finding is clinically
relevant because HAE is a debilitating disease, and patients
with frequent attacks have severe impairment in their quality
of life. Fur ther evidence for the convincing efficacy of C1-
INH 20 U/kg lies with the lack of any new at tack having
occurred in this treatment group before complete resolution of
the previous attack, indicating an absence of reboun d
angioedema.
The fact that C1-INH 10 U/kg did not show statistically
significant efficacy compared with placebo in our study, in
contrast with published data indicating the efficacy of this dose
or lower (eg, 500 U per attack, approximately 7 U/kg),
29-34
reflects
the more stringent criteria used for defining efficacy endpoints in
the confines of our double-blind, placebo-controlled study.
The safety analyses revealed no signals of concern, confirming
the favorable safety profile of C1-INH reported
previously.
8,30,32,33,35,36
A concern when administering plasma-
derived products is the potential risk for virus transmission to re-
cipients. During our study, consistent with 30 years of postmar-
keting surveillance data, there were no proven virus
seroconversions with C1-INH.
30,32
Therefore, we conclude that
the potential risk for viral transmission with the use of C1-INH
is minimal.
Our results show that C1-INH 20 U/kg administered intrave-
nously is a reliable and effective treatment for rapidly alleviating
symptoms of abdominal and facial HAE attacks. Efficacy of the
lower C1-INH dose of 10 U/kg was not statistically significant
compared with placebo. The recommended dose of C1-INH
concentrate in the treatment of acute HAE attacks is therefore 20
U/kg. Taken together, these data address the acknowledged need
for double-blind, placebo-controlled studies to assess appropriate
doses of novel therapies being investigated for the treatment of
HAE.
14
C1-INH provides an important contribution to the cur-
rently limited range of options for treating acute attacks in type
I or II HAE.
We thank all investigators, subinvestigators, and other members of the
I.M.P.A.C.T.1 study group at the following centers (in order of center
number), whose valuable contributions were essential to the success of this
study: Ralph Shapiro, MD, Midwest Immunology Clinic, Plymouth, Minn;
Timothy Craig, MD, Allergy and Respiratory Research, Penn State
University College of Medicine, Hershey, Pa; Againdra Bewtra, MD,
Creighton University School of Medicine, Omaha, Neb; Sami Bahna,
MD, Louisiana State University Health Sciences Center, Shreveport, La;
David Hurewitz, MD, Allergy Clinic of Tulsa, Inc, Tulsa, Okla; David
Elkayam, MD, Bellingham Asthma, Allergy and Immunology Clinic,
Bellingham, Wash; Jonathan Bernstein, MD, University of Cincinnati
Medical Center and Bernstein Clinical Research Center, Cincinnati, Ohio;
Lynda Schneider, MD, Division of Immunology, Children’s Hospital
Boston, Boston, Mass; Robyn Levy, MD, Family Allergy and Asthma
Center, PC, Atlanta, Ga; James Moy, MD, University Consultants in
Allergy and Immunology, Chicago, Ill; Richard Wasserman, MD, PhD,
Pediatric Allergy Immunology Associates, Dallas, Tex; Jacob Offenberger,
MD, Allergy and Asthma Relief Experts, Granada Hills, Calif; Arye
Rubinstein, MD, Montefiore Medical Center, Biomedical Research Alliance
of New York (BRANY) Albert Einstein College of Medicine, Bronx, NY;
Kraig Jacobson, MD, Allergy and Asthma Research Center, Eugene, Ore;
Bruce Ritchie, MD, Departments of Medicine and Medical Oncology, Uni-
versity of Alberta, Edmonton, Canada; William Yang, MD, FRCPC,
Asthma and Allergy Research Center, Ottawa, Ontario, Canada; Frank Ei-
delman, MD, Cleveland Clinic Florida, Weston, Fla; Gerti Janss, MD,
The Allergy Clinic, Rapid City, SD; Flint Packer, MD, Family First Medical
Center, Idaho Falls, Idaho; Hilary Longhurst, MD, Department of Immuno-
pathology, Barts and the London National Health Service Trust, London,
United Kingdom; Krystyna Obtulowicz, MD, Jagiellonian University Hos-
pital, Krakow, Poland; Marek Stopinski, MD, Oddzial Chorob Wewnetrz-
nych, Szpzoz Szpital Zachodni, Im. Jana Pawla II, Grodzisk Mazowiecki,
Poland; Maria Concepcio
´
nLo
´
pez-Serrano, MD, Servicio de Alergia, Hospi-
tal Universitario La Paz, Madrid, Spain; Henriette Farkas, MD, Semmel-
weis University Clinical Center, Allergy and Angioedema Outpatient
Clinic, Budapest, Hungary; Todor Shirov, MD, Tsarita Yoanna Hospital,
Ear, Nose, and Throat Clinic, Sofia, Bulgaria; Spas Konsulov, MD, Univer-
sity Hospital ‘St George’’, Ear, Nose, and Throat Department, Plovdiv, Bul-
garia; Natalia Ilina, MD, Institute of Immunology, Federal Medicobiologic
Agency, Moscow, Russia; Alexander Chuchalin, MD, Scientific and Re-
search Institute of Pulmonology, Federal Agency of Health and Social De-
velopment, Moscow, Russia; Ludmila Goryachina, MD, Russian Medical
Academy of Postgraduate Education, Moscow, Russia; Vesna Grivcheva-
Panovska, MD, PHI-University Clinical Center, Department of Dermatol-
ogy, Allergology and Clinical Immunology, Skopje, Republic of
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VOLUME nnn, NUMBER nn
CRAIG ET AL 7
ARTICLE IN PRESS
Macedonia; Janne Bjoerkander, MD, Sahlgrenska Universitetssjukhuset
Clinical Trial Center, Goeteborg, Sweden; Dumitru Moldovan, MD, 4th
Medical Clinic, University of Medicine and Pharmacy, Tirgu Mures, Roma-
nia; Jiri Litzman, MD, University Hospital St Anna, Brno Institute of Clin-
ical Immunology and Allergology, Brno, Czech Republic; Conne Katelaris,
MD, Westmead Specialist Centre, Westmead, Australia; Avner Reshef, MD,
Internal Medicine, Allergy and Immunology, Chaim Sheba Medical Center,
Tel Hashomer, Israel; and Alejandro Malbran, MD, Unidad de Alergia,
Asma e Immunologia Clinica, Buenos Aires, Argentina.
We also thank Dr Douglas Fiebig for providing medical writing
services to C SL B ehring on behalf of Trilogy Writing & Consulting
GmbH, and Silke Jasky-Gamb, Silke Kuhl, and Dirk Spruck for their
careful data management and statistical programming on behalf of
Accovion GmbH.
Clinical implications: C1 esterase inhibitor at a dose of 20 U/kg
is a reliable and effective treatment for rapidly alleviating
symptoms of HAE attacks, irrespective of body location or
severity.
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    • "The indications for the specific treatment of HAE attacks are well established. Plasma-derived C1INH and icatibant are the undisputed emergency drugs for life-threatening cases (laryngeal involvement), abdominal attacks and cases with facial involvement [2, 3, 20, 21]. Early home treatment is recommended [2, 15]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Despite the availability of guidelines for the specific treatment of hereditary angioedema (HAE) attacks, HAE morbidity and mortality rates remain substantial. HAE attacks are a major medical issue requiring specific treatment as well as a considerable socio-economic burden. We report a protocol designed to test whether a dedicated call centre is more effective than usual practice in the management of patients experiencing an HAE attack. Methods/design: This prospective, cluster-randomised, single-blind, parallel-group, multicentre trial evaluates the morbidity and consequent socio-economic costs of the management of patients experiencing an HAE attack by a dedicated call centre as compared to usual practice. The trial aims to recruit 200 patients. Patients in the intervention arm are provided with an SOS-HAE card with the call centre's freephone number that they can access in the case of an attack. The centre's mission is to provide recommended expert advice on early home treatment. The centre can route the call to a local emergency medical service with competency in HAE management or even arrange for the drugs needed for the specific treatment of an HAE attack to be sent to the emergency department of the local hospital. The primary outcome measure is the number of hospital admissions for an HAE attack. Each patient will be followed up every 2 months for 2 years. The study has been approved by the ethics committee (Comité de Protection des Personnes d'Ile de France 10; registration number: 2012-A00044-39; date of approval: 19 January 2012). Discussion: The SOS-HAE protocol has been designed to address the handling of attacks experienced by patients with HAE in the home. The proposed trial will determine whether the setting up of a dedicated call centre is more effective than usual practice in terms of reducing morbidity as given by the numbers of hospital admissions. The results are also anticipated to have important implications in terms of socio-economic costs for both healthcare services and patients. Trial registration: ClinicalTrials.gov NCT01679912 .
    Full-text · Article · Dec 2016
    • "This range in dosing can be explained by to the long duration of the study (19971998199920002001200220032004200520062007200820092010201120122013. 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. Prior to 2010 (when Berinert® was approved in Canada for acute attacks), the medication was only accessible through Health Canada's Special Access Programme on a case-by-case basis. "
    [Show abstract] [Hide abstract] 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
    • "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). "
    [Show abstract] [Hide abstract] 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
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