Subcutaneous C1 inhibitor for prevention of attacks of hereditary angioedema: Additional outcomes and subgroup analysis of a placebo-controlled randomized study

H. Henry Li, Bruce Zuraw, Hilary J. Longhurst, Marco Cicardi, Konrad Bork, James Baker, William Lumry, Jonathan Bernstein, Michael Manning, Donald Levy, Marc A. Riedl, Henrike Feuersenger, Subhransu Prusty, Ingo Pragst, Thomas Machnig, Timothy Craig

Research output: Contribution to journalArticle

Abstract

Background: Hereditary angioedema (HAE) is a debilitating disorder resulting from C1-esterase inhibitor (C1-INH) deficiency. In the COMPACT phase 3 study the prophylactic use of a subcutaneous C1 inhibitor (C1-INH [SC], HAEGARDA®, CSL Behring) twice weekly significantly reduced the frequency of acute edema attacks. Analysis of treatment effects by subgroups, onset of effect, and other exploratory analysis have not been reported. Methods: This is a post hoc exploratory analysis on data from the randomized, placebo-controlled COMPACT study. 90 patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH (SC) 40 or 60 IU/kg of body weight twice weekly for 16 weeks, preceded or followed by a placebo period. The pre-specified primary efficacy endpoint was the time-normalized number of HAE attacks, and pre-specified secondary efficacy endpoints were the percentage of patients with a certain treatment response (≥ 50% reduction on C1-INH (SC) versus placebo in the time-normalized number of attacks) and the time-normalized number of use of rescue medication. Pre-specified exploratory endpoints included severity of attacks, alone and combined with rescue medication use. Post hoc analyses included exploration of onset of effect and clinical assessment of patients with < 50% of response. Results: Subgroup findings by various patient characteristics showed a consistent preventive effect of C1-INH (SC). In a post hoc analysis of attacks, the onset of the preventive effect within the first 2 weeks after treatment initiation in COMPACT showed that 10/43 patients (23%) experienced attacks of any severity with 60 IU/kg versus 34/42 patients (81%) with placebo. The need for rescue medication was tenfold lower with 60 IU/kg (35 treated attacks) versus placebo (358 treated attacks). A qualitative analysis of the 4 patients treated with 60 IU/kg and with < 50% reduction of attacks demonstrated a reduction in severity of attacks, rescue medication use, and symptom days which was considered a clinically meaningful treatment effect. Conclusions: C1-INH (SC) prophylaxis demonstrated a preventive treatment effect with evidence of benefit within 2 weeks. A consistent treatment effect at recommended C1-INH (SC) dosing was evident in all subgroups of patients with type I/II HAE and by various measures of disease and treatment burden. Trial registration EU Clinical Trials Register, 2013-000916-10, Registered 10 December 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000916-10; ClinicalTrials.gov Register, NCT01912456, Registered 31 July 2013, https://clinicaltrials.gov/ct2/show/NCT01912456.

Original languageEnglish (US)
Article number49
JournalAllergy, Asthma and Clinical Immunology
Volume15
Issue number1
DOIs
StatePublished - Aug 28 2019

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Hereditary Angioedemas
Complement C1 Inhibitor Protein
Placebos
Therapeutics
Hereditary Angioedema Types I and II
Edema
Body Weight
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Pulmonary and Respiratory Medicine

Cite this

Li, H. Henry ; Zuraw, Bruce ; Longhurst, Hilary J. ; Cicardi, Marco ; Bork, Konrad ; Baker, James ; Lumry, William ; Bernstein, Jonathan ; Manning, Michael ; Levy, Donald ; Riedl, Marc A. ; Feuersenger, Henrike ; Prusty, Subhransu ; Pragst, Ingo ; Machnig, Thomas ; Craig, Timothy. / Subcutaneous C1 inhibitor for prevention of attacks of hereditary angioedema : Additional outcomes and subgroup analysis of a placebo-controlled randomized study. In: Allergy, Asthma and Clinical Immunology. 2019 ; Vol. 15, No. 1.
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abstract = "Background: Hereditary angioedema (HAE) is a debilitating disorder resulting from C1-esterase inhibitor (C1-INH) deficiency. In the COMPACT phase 3 study the prophylactic use of a subcutaneous C1 inhibitor (C1-INH [SC], HAEGARDA{\circledR}, CSL Behring) twice weekly significantly reduced the frequency of acute edema attacks. Analysis of treatment effects by subgroups, onset of effect, and other exploratory analysis have not been reported. Methods: This is a post hoc exploratory analysis on data from the randomized, placebo-controlled COMPACT study. 90 patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH (SC) 40 or 60 IU/kg of body weight twice weekly for 16 weeks, preceded or followed by a placebo period. The pre-specified primary efficacy endpoint was the time-normalized number of HAE attacks, and pre-specified secondary efficacy endpoints were the percentage of patients with a certain treatment response (≥ 50{\%} reduction on C1-INH (SC) versus placebo in the time-normalized number of attacks) and the time-normalized number of use of rescue medication. Pre-specified exploratory endpoints included severity of attacks, alone and combined with rescue medication use. Post hoc analyses included exploration of onset of effect and clinical assessment of patients with < 50{\%} of response. Results: Subgroup findings by various patient characteristics showed a consistent preventive effect of C1-INH (SC). In a post hoc analysis of attacks, the onset of the preventive effect within the first 2 weeks after treatment initiation in COMPACT showed that 10/43 patients (23{\%}) experienced attacks of any severity with 60 IU/kg versus 34/42 patients (81{\%}) with placebo. The need for rescue medication was tenfold lower with 60 IU/kg (35 treated attacks) versus placebo (358 treated attacks). A qualitative analysis of the 4 patients treated with 60 IU/kg and with < 50{\%} reduction of attacks demonstrated a reduction in severity of attacks, rescue medication use, and symptom days which was considered a clinically meaningful treatment effect. Conclusions: C1-INH (SC) prophylaxis demonstrated a preventive treatment effect with evidence of benefit within 2 weeks. A consistent treatment effect at recommended C1-INH (SC) dosing was evident in all subgroups of patients with type I/II HAE and by various measures of disease and treatment burden. Trial registration EU Clinical Trials Register, 2013-000916-10, Registered 10 December 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000916-10; ClinicalTrials.gov Register, NCT01912456, Registered 31 July 2013, https://clinicaltrials.gov/ct2/show/NCT01912456.",
author = "Li, {H. Henry} and Bruce Zuraw and Longhurst, {Hilary J.} and Marco Cicardi and Konrad Bork and James Baker and William Lumry and Jonathan Bernstein and Michael Manning and Donald Levy and Riedl, {Marc A.} and Henrike Feuersenger and Subhransu Prusty and Ingo Pragst and Thomas Machnig and Timothy Craig",
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language = "English (US)",
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journal = "Allergy, Asthma and Clinical Immunology",
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Li, HH, Zuraw, B, Longhurst, HJ, Cicardi, M, Bork, K, Baker, J, Lumry, W, Bernstein, J, Manning, M, Levy, D, Riedl, MA, Feuersenger, H, Prusty, S, Pragst, I, Machnig, T & Craig, T 2019, 'Subcutaneous C1 inhibitor for prevention of attacks of hereditary angioedema: Additional outcomes and subgroup analysis of a placebo-controlled randomized study', Allergy, Asthma and Clinical Immunology, vol. 15, no. 1, 49. https://doi.org/10.1186/s13223-019-0362-1

Subcutaneous C1 inhibitor for prevention of attacks of hereditary angioedema : Additional outcomes and subgroup analysis of a placebo-controlled randomized study. / Li, H. Henry; Zuraw, Bruce; Longhurst, Hilary J.; Cicardi, Marco; Bork, Konrad; Baker, James; Lumry, William; Bernstein, Jonathan; Manning, Michael; Levy, Donald; Riedl, Marc A.; Feuersenger, Henrike; Prusty, Subhransu; Pragst, Ingo; Machnig, Thomas; Craig, Timothy.

In: Allergy, Asthma and Clinical Immunology, Vol. 15, No. 1, 49, 28.08.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Subcutaneous C1 inhibitor for prevention of attacks of hereditary angioedema

T2 - Additional outcomes and subgroup analysis of a placebo-controlled randomized study

AU - Li, H. Henry

AU - Zuraw, Bruce

AU - Longhurst, Hilary J.

AU - Cicardi, Marco

AU - Bork, Konrad

AU - Baker, James

AU - Lumry, William

AU - Bernstein, Jonathan

AU - Manning, Michael

AU - Levy, Donald

AU - Riedl, Marc A.

AU - Feuersenger, Henrike

AU - Prusty, Subhransu

AU - Pragst, Ingo

AU - Machnig, Thomas

AU - Craig, Timothy

PY - 2019/8/28

Y1 - 2019/8/28

N2 - Background: Hereditary angioedema (HAE) is a debilitating disorder resulting from C1-esterase inhibitor (C1-INH) deficiency. In the COMPACT phase 3 study the prophylactic use of a subcutaneous C1 inhibitor (C1-INH [SC], HAEGARDA®, CSL Behring) twice weekly significantly reduced the frequency of acute edema attacks. Analysis of treatment effects by subgroups, onset of effect, and other exploratory analysis have not been reported. Methods: This is a post hoc exploratory analysis on data from the randomized, placebo-controlled COMPACT study. 90 patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH (SC) 40 or 60 IU/kg of body weight twice weekly for 16 weeks, preceded or followed by a placebo period. The pre-specified primary efficacy endpoint was the time-normalized number of HAE attacks, and pre-specified secondary efficacy endpoints were the percentage of patients with a certain treatment response (≥ 50% reduction on C1-INH (SC) versus placebo in the time-normalized number of attacks) and the time-normalized number of use of rescue medication. Pre-specified exploratory endpoints included severity of attacks, alone and combined with rescue medication use. Post hoc analyses included exploration of onset of effect and clinical assessment of patients with < 50% of response. Results: Subgroup findings by various patient characteristics showed a consistent preventive effect of C1-INH (SC). In a post hoc analysis of attacks, the onset of the preventive effect within the first 2 weeks after treatment initiation in COMPACT showed that 10/43 patients (23%) experienced attacks of any severity with 60 IU/kg versus 34/42 patients (81%) with placebo. The need for rescue medication was tenfold lower with 60 IU/kg (35 treated attacks) versus placebo (358 treated attacks). A qualitative analysis of the 4 patients treated with 60 IU/kg and with < 50% reduction of attacks demonstrated a reduction in severity of attacks, rescue medication use, and symptom days which was considered a clinically meaningful treatment effect. Conclusions: C1-INH (SC) prophylaxis demonstrated a preventive treatment effect with evidence of benefit within 2 weeks. A consistent treatment effect at recommended C1-INH (SC) dosing was evident in all subgroups of patients with type I/II HAE and by various measures of disease and treatment burden. Trial registration EU Clinical Trials Register, 2013-000916-10, Registered 10 December 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000916-10; ClinicalTrials.gov Register, NCT01912456, Registered 31 July 2013, https://clinicaltrials.gov/ct2/show/NCT01912456.

AB - Background: Hereditary angioedema (HAE) is a debilitating disorder resulting from C1-esterase inhibitor (C1-INH) deficiency. In the COMPACT phase 3 study the prophylactic use of a subcutaneous C1 inhibitor (C1-INH [SC], HAEGARDA®, CSL Behring) twice weekly significantly reduced the frequency of acute edema attacks. Analysis of treatment effects by subgroups, onset of effect, and other exploratory analysis have not been reported. Methods: This is a post hoc exploratory analysis on data from the randomized, placebo-controlled COMPACT study. 90 patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH (SC) 40 or 60 IU/kg of body weight twice weekly for 16 weeks, preceded or followed by a placebo period. The pre-specified primary efficacy endpoint was the time-normalized number of HAE attacks, and pre-specified secondary efficacy endpoints were the percentage of patients with a certain treatment response (≥ 50% reduction on C1-INH (SC) versus placebo in the time-normalized number of attacks) and the time-normalized number of use of rescue medication. Pre-specified exploratory endpoints included severity of attacks, alone and combined with rescue medication use. Post hoc analyses included exploration of onset of effect and clinical assessment of patients with < 50% of response. Results: Subgroup findings by various patient characteristics showed a consistent preventive effect of C1-INH (SC). In a post hoc analysis of attacks, the onset of the preventive effect within the first 2 weeks after treatment initiation in COMPACT showed that 10/43 patients (23%) experienced attacks of any severity with 60 IU/kg versus 34/42 patients (81%) with placebo. The need for rescue medication was tenfold lower with 60 IU/kg (35 treated attacks) versus placebo (358 treated attacks). A qualitative analysis of the 4 patients treated with 60 IU/kg and with < 50% reduction of attacks demonstrated a reduction in severity of attacks, rescue medication use, and symptom days which was considered a clinically meaningful treatment effect. Conclusions: C1-INH (SC) prophylaxis demonstrated a preventive treatment effect with evidence of benefit within 2 weeks. A consistent treatment effect at recommended C1-INH (SC) dosing was evident in all subgroups of patients with type I/II HAE and by various measures of disease and treatment burden. Trial registration EU Clinical Trials Register, 2013-000916-10, Registered 10 December 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000916-10; ClinicalTrials.gov Register, NCT01912456, Registered 31 July 2013, https://clinicaltrials.gov/ct2/show/NCT01912456.

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