icatibant, a selective bradykinin b2 receptor antagonist used in hereditary angioedema due to c1...
TRANSCRIPT
J ALLERGY CLIN IMMUNOL
VOLUME 125, NUMBER 2
Abstracts AB165
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646 C1 Esterase Inhibitor: Retrospective Validation of a CommonlyUsed Endpoint in Hereditary Angioedema Studies, Time toOnset of Relief, in a Global, Multicenter, Randomized,Placebo-Controlled Study (I.M.P.A.C.T.1)
A. Bewtra1, J. Bernstein2, B. Ritchie3, R. Levy4, R. Wasserman5, D. Hur-
ewitz6, K. Obtulowicz7, A. Reshef8, D. Moldovan9, T. Shirov10, V. Griv-
cheva-Panovska11, P. Kiessling12, H. Keinecke13, T. Craig14; 1Creighton
University School of Medicine, Omaha, NE, 2University of Cincinnati
Medical Center and Bernstein Clinical Research Center, Cincinnati,
OH, 3University of Alberta, Departments of Medicine and Medical Oncol-
ogy, Edmonton, AB, CANADA, 4Family Allergy and Asthma Center, At-
lanta, GA, 5Pediatric Allergy Immunology Associates, Dallas, TX,6Allergy Clinic of Tulsa, Inc., Tulsa, OK, 7Jagiellonian University Hospi-
tal, Krakow, POLAND, 8The Chaim Sheba Medical Center, Tel
Hashomer, ISRAEL, 9University of Medicine and Pharmacy, 4th Medical
Clinic, Tirgu Mures, ROMANIA, 10University Hospital, Sofia, BULGA-
RIA, 11PHI-University Clinical Center, Department of Dermatology, Al-
lergology and Clinical Immunology, Skopje, MACEDONIA, THE
FORMER YUGOSLAV REPUBLIC OF, 12CSL Behring, Marburg, GER-
MANY, 13Accovion GmbH, Marburg, GERMANY, 14Penn State Univer-
sity College of Medicine, Hershey, PA.
RATIONALE: C1 esterase inhibitor (C1-INH) replacement therapy is the
recommended treatment for acute attacks in hereditary angioedema
(HAE). Time to onset of symptom relief is a common primary endpoint
for efficacy but has never been validated by correlation analysis with the
course of HAE symptoms. We retrospectively validated the primary end-
point for the I.M.P.A.C.T.1 study.
METHODS: Ninety-eight abdominal attacks were treated with 10 or 20
U/kg body weight of a highly purified C1-INH concentrate (Berinert�),
or placebo. The primary endpoint was the time to onset of symptom relief,
as determined by patient responses to a standard question posed at appro-
priate intervals for up to 24 h after treatment. In addition patients assessed
the intensity of the HAE symptoms pain, nausea, vomiting, cramps, and di-
arrhea individually over time. By Spearman rank correlation, the primary
endpoint was compared with the time to first reduction a) of the intensity of
any symptom present at baseline, b) of the sum of symptom intensity
scores, and c) of the intensity of the last symptom present at baseline.
RESULTS: The time to first reduction of the last symptom present at base-
line had the highest correlation with the primary endpoint (0.77). The cor-
relation was considerably lower for the time to first reduction of symptom
intensity (0.60), and the time to first reduction of the sum of symptom in-
tensity scores (0.63).
CONCLUSIONS: A retrospective validation confirmed that the time to
onset of symptom relief, as determined by patients, is an appropriate end-
point for assessing the efficacy of C1-INH therapy.
647 Frequency and Types of Hereditary Angioedema Prodromes asReported by Patients
M. J. Prematta1, C. Laudadio2, T. Craig1; 1Penn State University, Milton
S. Hershey Medical Center, Hershey, PA, 2CSL Behring, King of Prussia, PA.
RATIONALE: Only limited amounts of data have been published about
prodromal symptoms associated with hereditary angioedema (HAE).
The goal of this study is to report data regarding prodromal symptoms pa-
tients experienced before an HAE exacerbation from two different surveys.
METHODS: Data were obtained from a retrospective and prospective
survey. IRB approval and written consent was obtained from all research
subjects. A prospective survey was administered to subjects with HAE en-
rolled in an open-label study of human pasteurized C1 esterase inhibitor
concentrate. Subjects were queried on the presence of prodromal symptoms
at the time they were seeking treatment. The retrospective survey was a four
page survey sent by mail to 158 HAE patients. The survey focused on
questions related to prodromal symptoms prior to the last HAE attack.
RESULTS: The prospective study included 253 attacks, and the retrospec-
tive study included 52 attacks. After combining datasets, data regarding
prodromes was obtained for 305 HAE exacerbations, and patients reported
the presence of a prodrome before 70.5% of exacerbations. The most
frequent prodromes experienced before an HAE exacerbation included fa-
tigue (45.2%); GI complaints (40.7%); muscle aches or flu-like symptoms
(25.9%); rash (21.0%); and numbness or tingling (10.5%).
CONCLUSIONS: Seventy and one half percent of patients reported pro-
dromal symptoms before HAE attacks. This high frequency suggests that
prodromal symptoms could be a reliable indication to begin treatment in
order to prevent an acute HAE attack.
648 Icatibant, a Selective Bradykinin B2 Receptor AntagonistUsed in Hereditary Angioedema Due to C1 Inhibitor Deficiency
K. Bork; University of Mainz, Mainz, GERMANY
RATIONALE: Icatibant is a novel bradykinin B2 receptor antagonist used
in hereditary angioedema. To present efficacy and safety data in daily prac-
tice outside of clinical trials.
METHODS: 10 patients (5 women, 5 men) with hereditary angioedema
received 30 mg icatibant subcutaneously for 10 acute attacks (6 abdominal
pain attacks, 3 arm swellings, and 1 facial swelling). Times between the be-
ginning of the attack, the injection, the first relief of symptoms and the end
of symptoms were determined and compared with 10 earlier attacks in the
same location per patient.
RESULTS: Time between attack onset and icatibant injection was 3.161.2
hours in the mean. The mean time between the injection and the first symp-
tom relief was 30616.4 minutes for abdominal attacks and 41.3614.4 min-
utes for skin swellings. In untreated attacks, the mean time to first symptom
relief was 26.26 9.2 hours in abdominal attacks and 46.6614.7 hours in
skin swellings. The total duration of the treated attacks was 18.8621.4
hours in abdominal attacks and 16.1614.2 hours in skin swellings. The du-
ration of untreated attacks was 796 44.3 hours in abdominal attacks and
81616.9 hours in skin swellings. One patient had a return of abdominal
symptoms 6 hours after the icatibant injection. Side effects included reac-
tions at the injection sites which resolved without medical intervention.
CONCLUSIONS: Treatment of acute attacks of hereditary angioedema in
daily practice confirms efficacy data of icatibant as shown in clinical trials.
649 Interim Results from Continuation-the Ongoing, Open-Label,Extension Study of Ecallantide for the Treatment of AcuteAttacks of Hereditary Angioedema
A. J. MacGinnitie1, W. E. Pullman2, P. T. Horn2; 1Childrens Hospital of
Pittsburgh of UPMC, Pittsburgh, PA, 2Dyax Corp, Cambridge, MA.
RATIONALE: Hereditary angioedema (HAE) is a rare and potentially fatal
disease characterized by unpredictable, acute swelling attacks. Interim re-
sults from the Continuation study (DX-88/19) of ecallantide, a novel plasma
kallikrein inhibitor, for the treatment of acute HAE attacks are reported.
METHODS: This is an ongoing, non-randomized, open-label study in pa-
tients with mild, moderate, or severe acute HAE attacks affecting any an-
atomic location. Patients can receive treatment for multiple attacks.
Efficacy endpoints include 2 validated, HAE-specific, patient-reported out-
come measures: Mean Symptom Complex Severity (MSCS) score and
Treatment Outcome Score (TOS). Interim efficacy data were analyzed
across treatment episodes 1 through 6.
RESULTS: Through 12 March 2009, 138 patients enrolled in DX-88/19;
95 received ecallantide for 278 total treatment episodes. Across treatment
episodes, mean change from baseline in MSCS score at 4 hours ranged
from -0.93 to -1.15, indicating significant symptom improvement.
Improvement was also demonstrated by mean 4-hour TOS scores of 54.3
to 68.3. The proportion of patients demonstrating significant improvement
at 4 hours ranged from 46.0% to 58.3%. Treatment-emergent adverse
events were generally mild or moderate and unrelated to ecallantide.
One anaphylaxis case and 2 cases of moderate/severe hypersensitivity (ur-
ticaria and chest discomfort/flushing) were reported; the patients recovered
without sequelae. All 3 patients were anti-ecallantide-antibody positive.
Eight additional cases of possible mild or moderate hypersensitivity (in-
volving urticaria, pruritus, flushing, or rash) were also reported.
CONCLUSIONS: This study provides further evidence that ecallantide is
efficacious for the treatment of acute HAE attacks, and the observed safety
profile remains unchanged.