A Study of Icatibant in Patients With Acute Attacks of Hereditary Angioedema (FAST-3)

• Time to Onset of Primary Symptom Relief [ Time Frame: Up to 120 hours post-dose ] [ Designated as safety issue: No ]
  Time to primary symptom relief was calculated from the time of study drug administration to the onset of primary symptom relief, where onset of primary symptom relief was determined using the subject-assessed VAS score for a single primary symptom (determined by edema location) and defined as the earliest of 3 consecutive non-missing measurements in which a pre-specified reduction from the pretreatment value was met. Subjects who did not achieve primary symptom relief within the observation period were censored at the last observation time.
• Time to Almost Complete Symptom Relief [ Time Frame: Up to 120 Hours post treatment ] [ Designated as safety issue: No ]
  Time to almost complete symptom relief was calculated from the time of study drug administration to almost complete symptom relief, where almost complete symptom relief was defined as the earliest of 3 consecutive non-missing measurements in which all VAS scores <10 mm. Subjects who did not achieve almost complete symptom relief within the observation period were censored at the last observation time.
• Time to Subject-Assessed Initial Symptom Improvement [ Time Frame: Up to 120 hours post-dose ] [ Designated as safety issue: No ]
  Time to initial symptom improvement was calculated from the time of study drug administration to initial symptom improvement as determined by the subject as the time they felt symptoms were starting to improve. Subjects who did not achieve initial symptom improvement within the observation period were censored at the last observation time.
• Time to Investigator-Assessed Initial Symptom Improvement [ Time Frame: Up to 120 hours post-dose ] [ Designated as safety issue: No ]
  Time to initial symptom improvement was calculated from the time of study drug administration to initial symptom improvement as determined by the investigator as the time they felt symptoms were starting to improve. Subjects who did not achieve initial symptom improvement within the observation period were censored at the last observation time.

• Change in VAS score from pretreatment [ Time Frame: 4 and 8 hours post-treatment ] [ Designated as safety issue: No ]
• Evaluation of global outcome of treatment using symptom severity score (by patient and investigator) [ Time Frame: Up to 12 hours post-treatment ] [ Designated as safety issue: No ]
• Assessment of global improvement(by patient and investigator) [ Time Frame: 4 and 8 hours post-treatment ] [ Designated as safety issue: No ]
• Global assessment of symptoms (by investigator) [ Time Frame: 4 and 8 hours post-treatment ] [ Designated as safety issue: No ]
• Time(s) to initial symptom improvement and almost complete symptom relief [ Time Frame: Up to 5 days post-treatment ] [ Designated as safety issue: No ]
• Safety and tolerability [ Time Frame: Up to 14 days post-treatment ] [ Designated as safety issue: Yes ]
• Time to reduction in symptom severity of laryngeal attacks [ Time Frame: Up to Day 5 post-treatment ] [ Designated as safety issue: No ]

This study is being conducted to evaluate the efficacy and safety of icatibant compared to placebo in patients experiencing acute attacks of hereditary angioedema (HAE).

This Phase III study consisted of two parts: A controlled phase and an open label extension (OLE) phase.

The controlled phase describes the double blind part of the study and was intended to evaluate the efficacy and safety of icatibant compared with placebo for the first treated cutaneous and/or abdominal attack.

Patients with moderate to severe abdominal or cutaneous attacks were randomized to receive a single, blinded, subcutaneous injection of icatibant (30 mg) or placebo. After a protocol amendment, patients with mild to moderate laryngeal HAE attacks were also randomized to receive a single, blinded subcutaneous injection of icatibant (30 mg) or placebo in order to obtain blinded, controlled efficacy and safety data for this subset of subjects. Patients experiencing severe laryngeal attacks (post-amendment) or mild to severe laryngeal attacks (pre-amendment) were to receive open-label icatibant.

After treatment of the first attack in the controlled phase, patients were eligible to enter the OLE phase. In the OLE phase, patients who experienced angioedema attacks severe enough to warrant treatment were to be treated with s.c. icatibant as appropriate until the study was discontinued or the product was commercially available.

• Drug: Icatibant
  Single subcutaneous injection of icatibant, 30 mg
  Other Name: Firazyr
• Drug: Placebo
  Single subcutaneous injection of matching placebo

• Placebo Comparator: Placebo
  Single subcutaneous injection of matching placebo
  Intervention: Drug: Placebo
• Experimental: Icatibant
  Single subcutaneous injection of icatibant, 30 mg
  Intervention: Drug: Icatibant

• Maurer M, Longhurst HJ, Fabien V, Li HH, Lumry WR. Treatment of hereditary angioedema with icatibant: efficacy in clinical trials versus effectiveness in the real-world setting. Allergy Asthma Proc. 2014 Sep-Oct;35(5):377-81. doi: 10.2500/aap.2014.35.3780. Epub 2014 Aug 6.
• Baş M. Clinical efficacy of icatibant in the treatment of acute hereditary angioedema during the FAST-3 trial. Expert Rev Clin Immunol. 2012 Nov;8(8):707-17. doi: 10.1586/eci.12.67.
• Lumry WR, Li HH, Levy RJ, Potter PC, Farkas H, Moldovan D, Riedl M, Li H, Craig T, Bloom BJ, Reshef A. Randomized placebo-controlled trial of the bradykinin B₂ receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol. 2011 Dec;107(6):529-37. doi: 10.1016/j.anai.2011.08.015. Epub 2011 Oct 5.

Inclusion Criteria:

Each patient must meet the following criteria to be enrolled in this study.

1. The patient is ≥18 years old at the time of informed consent.
2. The patient has a documented diagnosis of HAE type I or II. The diagnosis will be confirmed either by documented decreased C4 levels and/or immunogenic or functional C1-INH deficiency results (<50% of normal levels) consistent with HAE types I and II or by medical history.
3. The current HAE attack must be in the cutaneous, abdominal and/or laryngeal (inclusive of laryngeal and pharyngeal) areas.
4. Cutaneous or abdominal HAE attacks must be moderate to very severe as determined by investigator global assessment at pre-treatment assessments
5. The patient must report at least 1 VAS score ≥ 30mm
6. The patient commences treatment within 6 hours of the attack becoming at least mild (laryngeal) or moderate (non-laryngeal) in severity, but not more than 12 hours after the onset of the attack.
7. Women of childbearing potential must have a negative urine pregnancy test and must use appropriate methods to prevent pregnancy during their participation in the study.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from the study.

1. The patient has a diagnosis of angioedema other than HAE type I or II.
2. The patient has received previous treatment with icatibant.
3. The patient has participated in a clinical trial and has received treatment with another investigational medicinal product within the past 30 days.
4. The patient has received treatment with any pain medication since the onset of the current angioedema attack.
5. The patient has received replacement therapy (fresh frozen plasma [FFP], C1-INH products) less than 5 days (120 hours) from the onset of the current angioedema attack.
6. The patient is receiving treatment with angiotensin converting enzyme (ACE) inhibitors.
7. Evidence of coronary artery disease based on medical history or screening examination in particular unstable angina pectoris or severe coronary heart disease;
8. The patient has a serious concomitant illness or condition that, in the opinion of the Investigator, would be a contraindication for participation in the trial.
9. The patient is pregnant or breastfeeding.