TY - JOUR
T1 - Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor
AU - Longhurst, Hilary
AU - Cicardi, Marco
AU - Craig, Timothy
AU - Bork, Konrad
AU - Grattan, Clive
AU - Baker, James
AU - Li, Huamin H.
AU - Reshef, Avner
AU - Bonner, James
AU - Bernstein, Jonathan A.
AU - Anderson, John
AU - Lumry, William R.
AU - Farkas, Henriette
AU - Katelaris, Constance H.
AU - Sussman, Gordon L.
AU - Jacobs, Joshua
AU - Riedl, Marc
AU - Manning, Michael E.
AU - Hebert, Jacques
AU - Keith, Paul K.
AU - Kivity, Shmuel
AU - Neri, Sergio
AU - Levy, Donald S.
AU - Baeza, Maria L.
AU - Nathan, Robert
AU - Schwartz, Lawrence B.
AU - Caballero, Teresa
AU - Yang, William
AU - Crisan, Ioana
AU - Hernandez, Maria D.
AU - Hussain, Iftikhar
AU - Tarzi, Michael
AU - Ritchie, Bruce
AU - Kraličkova, Pavlina
AU - Guilarte, Mar
AU - Rehman, Syed M.
AU - Banerji, Aleena
AU - Gower, Richard G.
AU - Bensen-Kennedy, Debra
AU - Edelman, Jonathan
AU - Feuersenger, Henrike
AU - Lawo, John Philip
AU - MacHnig, Thomas
AU - Pawaskar, Dipti
AU - Pragst, Ingo
AU - Zuraw, Bruce L.
N1 - Publisher Copyright:
© 2017 Massachusetts Medical Society. All rights reserved.
PY - 2017/3/23
Y1 - 2017/3/23
N2 - BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks.
AB - BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks.
UR - http://www.scopus.com/inward/record.url?scp=85016299369&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1613627
DO - 10.1056/NEJMoa1613627
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AN - SCOPUS:85016299369
SN - 0028-4793
VL - 376
SP - 1131
EP - 1140
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 12
ER -