Hereditary angioedema: Validation of the end point time to onset of relief by correlation with symptom intensity.
Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy.
Department of Internal Medicine, University of Cincinnati College of Medicine, Ohio 45267-0563, USA. bernstja@ucmail.uc.edu
Jonathan A
JA
Bernstein
Bruce
B
Ritchie
Robyn J
RJ
Levy
Richard L
RL
Wasserman
Againdra K
AK
Bewtra
David S
DS
Hurewitz
Krystyna
K
Obtułowicz
Avner
A
Reshef
Dumitru
D
Moldovan
Todor
T
Shirov
Vesna
V
Grivcheva-Panovska
Peter C
PC
Kiessling
Heinz-Otto
HO
Keinecke
Timothy J
TJ
Craig
D054179:Angioedemas, Hereditary / Q000188:drug therapy*; D050718:Complement C1 Inhibitor Protein / Q000008:administration & dosage / Q000627:therapeutic use*; D023381:Endpoint Determination; D006801:Humans; D053208:Kaplan-Meier Estimate; D012189:Retrospective Studies; D016896:Treatment Outcome
D050718:Complement C1 Inhibitor Protein