Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial

doi:10.1016/j.anai.2011.08.015

Annals of Allergy, Asthma & Immunology

Volume 107, Issue 6, December 2011, Pages 529-537.e2

https://doi.org/10.1016/j.anai.2011.08.015 Get rights and content

Background

The For Angioedema Subcutaneous Treatment (FAST)-3 study was a phase III, randomized, double-blind, placebo-controlled study of icatibant (bradykinin B₂ receptor antagonist) in subjects with hereditary angioedema (HAE) resulting from C1-INH deficiency or dysfunction (type I/II).

Objective

To investigate icatibant efficacy and safety in subjects with acute HAE attacks.

Methods

Subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n = 43) or placebo (n = 45). Five subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n = 3) or placebo (n = 2), and 5 subjects with severe laryngeal first attacks received open-label icatibant.

Results

Cutaneous or abdominal attacks: icatibant significantly reduced median times (vs placebo) to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001, primary endpoint), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001, key secondary endpoint), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012) and provided a shorter time to initial symptom relief (0.8 vs 3.5 hours; P < .001). For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo). No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively). All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs.

Conclusions

FAST-3 demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks.

Trial Registration

Clinicaltrials.gov Identifier: NCT00912093.

Introduction

Hereditary angioedema (HAE) attributable to C1-esterase inhibitor (C1-INH) deficiency can result in elevated plasma and tissue levels of bradykinin,1, 2, 3, 4 a key mediator of swelling and pain associated with an HAE attack.5, 6 Attacks are debilitating and painful, and laryngeal attacks can be life-threatening.⁷ The inhibition of bradykinin action on vascular endothelium represents a feasible therapeutic strategy for treating acute HAE attacks.⁸

The clinical efficacy of icatibant, a potent bradykinin B₂ receptor antagonist, in the treatment of acute HAE attacks was investigated in the controlled For Angioedema Subcutaneous Treatment (FAST)-1 and FAST-2 phase III clinical studies.⁹ Although FAST-2 demonstrated superior efficacy to tranexamic acid for the primary endpoint, this was not seen in the placebo-controlled FAST-1 study. Carefully considered post hoc analyses identified several possible reasons, in particular that early use of rescue medications by placebo patients may have obscured the benefit of icatibant in FAST-1.⁹

The FAST-3 study was designed to evaluate the efficacy and safety of icatibant compared with placebo when administered subcutaneously. Results from the controlled phase of the FAST-3 study are presented.

Section snippets

Study Design

FAST-3 was a phase III, double-blind, randomized, placebo-controlled, multicenter study conducted at 67 centers in 11 countries (eMaterials section) in compliance with US Food and Drug Administration Institutional Review Board regulations, International Conference on Harmonisation Good Clinical Practice guidelines, and the Declaration of Helsinki. The protocol, protocol amendments, and patient informed consent forms were reviewed and approved by the institutional review board at each

Study Group Characteristics

Overall, 369 subjects were screened, and 98 were enrolled to receive study medication. Ninety-three had attacks qualifying them for randomization: 88 subjects with nonlaryngeal first attacks received icatibant (n = 43) or placebo (n = 45); 5 subjects with laryngeal (mild-to-moderate) attacks received icatibant (n = 3) or placebo (n = 2). Five additional subjects with severe laryngeal attacks received open-label icatibant (Fig 1). Subject characteristics are shown in Table I.

Cutaneous and Abdominal Attacks in the Nonlaryngeal Intent-to-Treat (ITT) Population

Median time to 50%

Discussion

The FAST-3 study demonstrated that subcutaneously administered icatibant 30 mg was effective in the treatment of acute angioedema attacks in adults with HAE types I and II. FAST-3 achieved its primary endpoint, with icatibant providing a significantly shorter time to symptom relief based on composite VAS score, and also a shorter time to onset of primary symptom relief, the key secondary endpoint for cutaneous and abdominal attacks (each P < .001 vs placebo). Additionally, for cutaneous and

Acknowledgments

The authors thank the study participants, staff, and co-investigators at participating centers and all collaborators on the sponsor's side.

Co-Principal investigators: Ajmani A, Bahna S, Baker J, Banerji A, Bernstein JA, Bleasel K, Bonner J, Busse P, Buyukozturk S, Cook M, Davis-Lorton M, Diaz JD, Emelyanov A, Fasano MB, Frank M, Gleich G, Gonzalez-Diaz S, Goryachkina L, Grant JA, Hebert J, Hogan MB, Hurewitz D, Huston D, Ivanovna Tsyvkina G, Johnson C, Kanuga J, Karakaya G, Katelaris C,

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Citation Excerpt :
The safety profile of icatibant in the current analysis was comparable between patients with HAE-1/2 and those with HAE nC1-INH; injection site-related reactions were the most frequently reported AEs. Findings are consistent with the icatibant safety profile reported in pivotal controlled trials in patients with HAE-1/236,37 as well as in other post-marketing analyses of IOS patients and icatibant-treated patients with HAE nC1-INH in non-controlled studies.29,34,38 Various limitations are inherent in an observational study design, including a lack of treatment comparator and reliance on patient recall, potentially leading to underreporting of milder attacks or incomplete reporting of symptoms.
Hereditary angioedema can be caused by C1-Inhibitor (C1-INH) deficiency and/or dysfunction (HAE-1/2) or can occur in patients with normal C1-INH (HAE nC1-INH).
The Icatibant Outcome Survey (IOS; NCT01034969) registry monitors the safety and effectiveness of icatibant for treating acute angioedema.
Present findings from Brazilian patients with HAE-1/2 and HAE nC1-INH participating in IOS.
42 patients were enrolled (HAE-1/2, n = 26; HAE nC1-INH, n = 16). Median age at symptom onset was significantly lower with HAE-1/2 vs. HAE nC1-INH (10.0 vs. 16.5y, respectively; p = 0.0105), whereas median age at diagnosis (31.1 vs. 40.9y; p = 0.1276) and the median time between symptom onset and diagnosis (15.0 vs. 23.8y; p = 0.6680) were numerically lower vs. HAE nC1-INH, respectively. One icatibant dose was used for > 95% of HAE attacks. Median (range) time-to-event outcomes were shorter for patients with HAE nC1-INH vs. HAE-1/2, including time to first administration (0.5 [0–96.0] vs. 1.0 [0–94.0]h, respectively), time from first administration to complete resolution (1.0 [0–88.0] vs. 5.5 [0–96.0]h, respectively), and total attack duration (7.0 [0.3–99.0] vs. 18.5 [0.1–100.0]h, respectively). Mean (SD) time from attack onset to resolution was significantly shorter for patients with HAE nC1-INH vs. HAE-1/2 (9.8 [18.7] vs. 19.6 [24.0]h, respectively; p = 0.0174). 83 adverse events (AEs) in 42 patients were reported; most were mild (66.3%) or moderate (13.3%) and non-serious (75.9%). The most common icatibant-related AE was injection site erythema (HAE-1/2, 34.6%; HAE nC1-INH, 18.8%).
This was an observational study without a treatment comparator and that relied on patient recall.
Findings demonstrate effectiveness and tolerability of icatibant in Brazilian HAE patients.

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: Disclosures: William Lumry speaks for CSL Behring, Dyax, and Viropharma. He has received research grant support from CSL Behring, Dyax, Shire HGT/Jerini AG, Pharming NV, and Viropharma. He is an advisor to CSL Behring, Dyax, Shire HGT/Jerini AG, and Viropharma.

: H. Henry Li speaks for CSL Behring, Dyax, and ViroPharma. He has received research grant support from CSL Behring, Dyax, Shire HGT/Jerini AG, Pharming NV, and ViroPharma. He also serves as a consultant/advisor to CSL Behring, Dyax, Shire HGT/Jerini AG, and ViroPharma.

: Robyn Levy speaks for CSL Behring. She has received research grant support from CSL Behring, Dyax, Shire HGT, Pharming Technologies BV, and Viropharma, Inc. She is a medical consultant for CSL Behring and Shire HGT.

: Paul C. Potter has no potential conflicts of interest to disclose.

: Henriette Farkas speaks for CSL Behring and Shire HGT/Jerini and has received travel grants and consultancy fees from CSL Behring, Pharming NV, Viropharma, and Shire HGT/Jerini AG.

: Dumitru Moldovan has received research fees from CSL Behring, Pharming Technologies, and Shire.

: Marc Riedl has performed research for CSL Behring, Dyax, Shire HGT, Pharming, and Viropharma, participated on Scientific Advisory boards for CSL Behring, Dyax, Shire HGT, and Viropharma, and has been a speaker for CSL Behring, Dyax, and Viropharma.

: Tim Craig speaks for CSL Behring, Dyax, and Viropharma and has performed research for CSL Behring, Dyax, Pharming NV, Shire HGT, and Viropharma.

: Bradley J. Bloom and Hongbin Li are employees of Shire HGT, Inc.

: Avner Reshef has received research grants from CSL Behring, Jerini AG/Shire HGT, and Pharming NV. Dr. Reshef is a member of the Global Advisory Board for Shire HGT.

: Funding Sources: The FAST-3 study, part of the clinical trial program of icatibant, was funded by Jerini AG/Shire Human Genetic Therapies, Inc.

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Original articleInterventionRandomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial