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

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00912093
• Collaborator: (none)
• Enrollment: 98
• Locations: 64
• Arms: 2
• Actual Duration (Months): 14.5
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Hereditary Angioedema	Drug: Icatibant; Drug: Placebo	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 98 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized, Double-Blind,Placebo-Controlled, Multicenter Study of Icatibant for Subcutaneous Injection in Patients With Acute Attacks of Hereditary Angioedema (HAE)
• Actual Study Start Date: Jul 16, 2009
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Single subcutaneous injection of matching placebo	Drug: Placebo; Single subcutaneous injection of matching placebo
Experimental: Icatibant Single subcutaneous injection of icatibant, 30 mg	Drug: Icatibant; Single subcutaneous injection of icatibant, 30 mg; Other Names: Firazyr

Outcome Measures

Primary Outcome Measures

1. Time to Onset of Symptom Relief for an Acute Attack, as Assessed by the Patient [Up to 120 hours post-dose]

   Time to onset of symptom relief was calculated from study drug administration to onset of symptom relief, where onset of symptom relief was defined as the earliest of 3 consecutive measurements in which there was a 50% reduction from pretreatment in composite VAS score. Composite VAS score comprised 3 symptoms, including skin swelling, skin pain, and abdominal pain, for cutaneous and abdominal attacks and 5 symptoms, including skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice change, for laryngeal attacks. Subjects who did not achieve symptom relief within the observation period were censored at the last observation time.

Secondary Outcome Measures

1. Time to Onset of Primary Symptom Relief [Up to 120 hours post-dose]

   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.

2. Time to Almost Complete Symptom Relief [Up to 120 Hours post treatment]

   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.

3. Time to Subject-Assessed Initial Symptom Improvement [Up to 120 hours post-dose]

   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.

4. Time to Investigator-Assessed Initial Symptom Improvement [Up to 120 hours post-dose]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Primary Care Associates of Alabaster	Alabaster	Alabama	United States	35007
2	UAB Lung Health Center	Birmingham	Alabama	United States	35294
3	Medical Research of AZ A Division of Allergy & Immunology Assoc	Scottsdale	Arizona	United States	85251
4	Little Rock Allergy & Asthma Clinic, PA	Little Rock	Arkansas	United States	72205
5	Allergy and Asthma Insititute of the Valley	Granada Hills	California	United States	91344
6	University of California San Diego	La Jolla	California	United States	92093
7	UCLA - Clinical Immunology & Allergy	Los Angeles	California	United States	90095
8	Speciality Medical Clinic & Research Center	Stanford	California	United States	27330
9	Standford University	Stanford	California	United States	94305
10	Asthma & Allergy Associates, PC	Colorado Springs	Colorado	United States	80907
11	Medical Associates of Brevard	Melbourne	Florida	United States	32935
12	University of South Florida Division of Allergy and Immunology	Tampa	Florida	United States	33613
13	Family Allergy and Asthma Center, PC	Atlanta	Georgia	United States	30342
14	Rush University Medical Center	Chicago	Illinois	United States	60612
15	Research Institute of Deaconess Clinic	Evansville	Indiana	United States	47713
16	University of Iowa Asthma Center/ Hospitals & Clinics	Iowa City	Iowa	United States	52242
17	LSUHSC Allergy & Immunology	Shreveport	Louisiana	United States	71130
18	Institute for Asthman & Allergy, P.C.	Chevy Chase	Maryland	United States	20815-6901
19	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
20	The Asthma Center	Saint Louis	Missouri	United States	63141
21	University of Reno Nevada School of Medicine	Reno	Nevada	United States	89503
22	STARx Research Center, LLC	Edison	New Jersey	United States	08820
23	Montefiore Medical Center/Albert Einstein College of Medicine	Bronx	New York	United States	10461
24	Winthrop University Hospital Clinical Trials Center	Mineola	New York	United States	11501
25	Mount Sinai School of Medicine	New York	New York	United States	10029
26	Allergy Partners of Western North Carolina	Asheville	North Carolina	United States	28801
27	Duke University Medical Center	Durham	North Carolina	United States	27710
28	University of Cincinnati Division of Immunology/Allergy	Cincinnati	Ohio	United States	45267
29	Optimed Research, LTD	Columbus	Ohio	United States	43235
30	Tulsa Allergy Clinic	Tulsa	Oklahoma	United States	74133
31	Baker Allergy, Asthma & Dermatology Research Center LLC	Lake Oswego	Oregon	United States	97035
32	Valley Clinical Research Center	Bethlehem	Pennsylvania	United States	18020
33	Penn State Hershey Medical Center	Hershey	Pennsylvania	United States	17033
34	Children's Hospital of Pittsburgh (of UMPC)	Pittsburgh	Pennsylvania	United States	15224
35	AARA Research Center	Dallas	Texas	United States	75231
36	University of Texas Medical Branch (UTMB)	Galveston	Texas	United States	77555-0561
37	Texas A&M Health Science Center College of Medicine	Houston	Texas	United States	77030
38	Allergy and Asthma Research Center, P.A.	San Antonio	Texas	United States	78229
39	University of Utah	Salt Lake City	Utah	United States	84132
40	Canberra Hospital Department of Immunology	Garran	Australian Capital Territory	Australia
41	Dept of Medicine Immunology & Allergy Campbelltown Hospital	Campbelltown	New South Wales	Australia	2560
42	Royal Melbourne Hospital Department of Immunology	Parkville	Victoria	Australia	3050
43	Royal Adelaide Hospital	Adelaide		Australia
44	NACTRC	Edmonton	Alberta	Canada	T6G 2H7
45	Allergy & Asthma Research Centre	Ottawa	Ontario	Canada	K1Y 4G2
46	Centre de recherché Appliquée en allergie de Québec	Quebec City	Quebec	Canada	G1V 5M6
47	3rd Department of Internal Medicine Semmelweis University	Budapest		Hungary	1125
48	Bnai-Zion Medical Center Division of Immunology & Allergy	Haifa		Israel	31048
49	Tel Aviv Medical Center	Tel Aviv		Israel	64239
50	The Chaim Sheba Medical Center	Tel Hashomer		Israel	52621
51	Spitalul Clinic Judetean Mures Sectia Medicina Interna	Targu Mures	Transylvania	Romania	540103
52	Medical Academy of Postgraduate Education	St Petersburg	Saint Petersburg	Russian Federation	194291
53	Autonomous Non Commercial Organization	St Petersburg	Saint Petersburg	Russian Federation	198216
54	State Healthcare Institution of City of Moscow	Moscow		Russian Federation	115446
55	State Enterprise State Scientific Centre	Moscow		Russian Federation	115478
56	State Educational Institution of Additional Profess. Edu. Moscow	Moscow		Russian Federation	123182
57	Municipal Medical & Preventive Treatment Institution	Smolensk		Russian Federation	214001
58	Regional Clinical Center of Specialized Medical Treatment	Vladivostok		Russian Federation	690091
59	Allergy Diagnostic and Clinical Research Unit (ADCRU)	Cape Town	Mowbray	South Africa	7700
60	Ivano-Frankivsk national Medical University	Ivano-Frankivsk		Ukraine	76018
61	National Medical Academy for Postgraduate Education	Kyiv		Ukraine	01133
62	Institute of Otolaryngology	Kyiv		Ukraine	03680
63	Ukranian Medical Stomatological Academy Dept of Int Diseases	Poltava		Ukraine	36039
64	Vinnitsa Medical Academy Chair of Internal Disease	Vinnitsa		Ukraine	21029

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00912093
• Other Study ID Numbers: HGT-FIR-054; 2009-015606-19
• First Posted: Jun 3, 2009
• Last Update Posted: Jun 11, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by Shire: HAE; Type I HAE; Type II HAE
• Additional relevant MeSH terms: Angioedema; Angioedemas, Hereditary; Icatibant

Study Results

Participant Flow

Arm/Group Title	Randomized-Icatibant (Blinded Treatment)-Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal	Randomized-Icatibant (Blinded Treatment)-Laryngeal	Randomized-Placebo (Blinded Treatment)-Laryngeal	Open-Label Icatibant-Severe Laryngeal
Arm/Group Description	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of icatibant, 30 mg in the controlled phase	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase	Subjects with mild to moderate laryngeal attacks of HAE randomized to receive a single subcutaneous injection of icatibant, 30 mg in the controlled phase	Subjects with mild to moderate laryngeal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase	Subjects with severe (post-amendment) or mild to severe (pre-amendment) laryngeal attacks of HAE treated with subcutaneous injection of icatibant, 30 mg in the controlled phase
Period Title: The Controlled Phase
STARTED	43	45	3	2	5
COMPLETED	43	43	3	2	4
NOT COMPLETED	0	2	0	0	1
Period Title: The Controlled Phase
STARTED	38	35	3	2	4
COMPLETED	38	35	3	2	4
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal	Randomized-Icatibant (Blinded Treatment)--Laryngeal	Randomized-Placebo (Blinded Treatment)-Laryngeal	Open-Label Icatibant-Severe Laryngeal	Total
Arm/Group Description	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of icatibant 30 mg in the controlled phase	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase	Subjects with mild to moderate laryngeal attacks of HAE randomized to receive a single subcutaneous injection of icatibant 30 mg in the controlled phase	Subjects with mild to moderate laryngeal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase	Subjects with severe (post-amendment) or mild to severe (pre-amendment) laryngeal attacks of HAE treated with subcutaneous injection of icatibant 30 mg in the controlled phase	Total of all reporting groups
Overall Participants	43	45	3	2	5	98
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.1 (13.69)	36.6 (11.18)	40.3 (6.66)	50.0 (22.63)	41.6 (11.78)	37.0 (12.46)
Sex: Female, Male (Count of Participants)
Female	27 62.8%	29 64.4%	2 66.7%	1 50%	2 40%	61 62.2%
Male	16 37.2%	16 35.6%	1 33.3%	1 50%	3 60%	37 37.8%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	3 7%	0 0%	0 0%	0 0%	0 0%	3 3.1%
Native Hawaiian or Other Pacific	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	38 88.4%	40 88.9%	3 100%	2 100%	4 80%	87 88.8%
Other	2 4.7%	5 11.1%	0 0%	0 0%	1 20%	8 8.2%
Region of Enrollment (Count of Participants)
United States	26 60.5%	32 71.1%	2 66.7%	2 100%	3 60%	65 66.3%
Hungary	3 7%	1 2.2%	0 0%	0 0%	0 0%	4 4.1%
Canada	1 2.3%	0 0%	0 0%	0 0%	0 0%	1 1%
Ukraine	0 0%	1 2.2%	0 0%	0 0%	0 0%	1 1%
Romania	3 7%	1 2.2%	1 33.3%	0 0%	0 0%	5 5.1%
Australia	2 4.7%	3 6.7%	0 0%	0 0%	0 0%	5 5.1%
Russian Federation	2 4.7%	1 2.2%	0 0%	0 0%	0 0%	3 3.1%
South Africa	2 4.7%	1 2.2%	0 0%	0 0%	1 20%	4 4.1%
Israel	4 9.3%	5 11.1%	0 0%	0 0%	1 20%	10 10.2%
Weight (kg) (Count of Participants)
<= 50 kg	4 9.3%	2 4.4%	0 0%	0 0%	0 0%	6 6.1%
>50-75 kg	16 37.2%	20 44.4%	1 33.3%	2 100%	0 0%	39 39.8%
>75-100 kg	14 32.6%	13 28.9%	1 33.3%	0 0%	3 60%	31 31.6%
>100 kg	9 20.9%	10 22.2%	1 33.3%	0 0%	2 40%	22 22.4%

Outcome Measures

1. Primary Outcome

Title	Time to Onset of Symptom Relief for an Acute Attack, as Assessed by the Patient
Description	Time to onset of symptom relief was calculated from study drug administration to onset of symptom relief, where onset of symptom relief was defined as the earliest of 3 consecutive measurements in which there was a 50% reduction from pretreatment in composite VAS score. Composite VAS score comprised 3 symptoms, including skin swelling, skin pain, and abdominal pain, for cutaneous and abdominal attacks and 5 symptoms, including skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice change, for laryngeal attacks. Subjects who did not achieve symptom relief within the observation period were censored at the last observation time.
Time Frame	Up to 120 hours post-dose

Outcome Measure Data

Analysis Population Description

Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.

Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal
Arm/Group Description	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of icatibant 30 mg in the controlled phase	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase
Measure Participants	43	45
Median (95% Confidence Interval) [Hours]	2.0	19.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Peto-Peto Wilcoxon
	Comments

2. Secondary Outcome

Title	Time to Onset of Primary Symptom Relief
Description	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 Frame	Up to 120 hours post-dose

Outcome Measure Data

Analysis Population Description

Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.

Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal
Arm/Group Description	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of icatibant 30 mg in the controlled phase	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase
Measure Participants	43	45
Median (95% Confidence Interval) [Hours]	1.5	18.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Peto-Peto Wilcoxon
	Comments

3. Secondary Outcome

Title	Time to Almost Complete Symptom Relief
Description	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 Frame	Up to 120 Hours post treatment

Outcome Measure Data

Analysis Population Description

Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.

Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal
Arm/Group Description	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of icatibant 30 mg in the controlled phase	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase
Measure Participants	43	45
Median (95% Confidence Interval) [Hours]	8.0	36.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Peto Peto Wilcoxon
	Comments

4. Secondary Outcome

Title	Time to Subject-Assessed Initial Symptom Improvement
Description	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 Frame	Up to 120 hours post-dose

Outcome Measure Data

Analysis Population Description

Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.

Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal
Arm/Group Description	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of icatibant 30 mg in the controlled phase	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase
Measure Participants	43	45
Median (95% Confidence Interval) [Hours]	0.8	3.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Peto-Peto Wilcoxon
	Comments

5. Secondary Outcome

Title	Time to Investigator-Assessed Initial Symptom Improvement
Description	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.
Time Frame	Up to 120 hours post-dose

Outcome Measure Data

Analysis Population Description

Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.

Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal
Arm/Group Description	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of icatibant 30 mg in the controlled phase	Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase
Measure Participants	43	45
Median (95% Confidence Interval) [Hours]	0.8	3.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Peto-Peto Wilcoxon
	Comments

Adverse Events

Time Frame	Treatment emergent adverse events occurring within 16 days of study drug administration are included in the analysis
Adverse Event Reporting Description	Subjects were analyzed according to the treatment actual received
Arm/Group Title	Controlled Phase - Icatibant (Randomized)		Controlled Phase -Placebo (Randomized)		Controlled Phase - Icatibant (Open Label)		Open Label Extension - Icatibant (Open Label)
Arm/Group Description	Subjects who were randomized to treatment and received a single subcutaneous injection of icatibant 30 mg in the controlled phase		Subjects who were randomized to treatment and received a single subcutaneous injection of matching placebo in the controlled phase		Subjects who were not randomized and received a single subcutaneous injection of icatibant 30 mg in the controlled phase		Subjects who treated with icatibant 30 mg in the open label extension phase
All Cause Mortality
	Controlled Phase - Icatibant (Randomized)		Controlled Phase -Placebo (Randomized)		Controlled Phase - Icatibant (Open Label)		Open Label Extension - Icatibant (Open Label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Controlled Phase - Icatibant (Randomized)		Controlled Phase -Placebo (Randomized)		Controlled Phase - Icatibant (Open Label)		Open Label Extension - Icatibant (Open Label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		5/46 (10.9%)		0/6 (0%)		7/82 (8.5%)
Cardiac disorders
Myocardial infarction	0/46 (0%)	0	1/46 (2.2%)	1	0/6 (0%)	0	0/82 (0%)	0
Arrhythmia	0/46 (0%)	0	0/46 (0%)	0	0/6 (0%)	0	1/82 (1.2%)	1
Congenital, familial and genetic disorders
Hereditary angioedema	0/46 (0%)	0	2/46 (4.3%)	2	0/6 (0%)	0	3/82 (3.7%)	3
General disorders
Non-Cardiac Chest Pain	0/46 (0%)	0	0/46 (0%)	0	0/6 (0%)	0	1/82 (1.2%)	1
Hepatobiliary disorders
Cholecystitis	0/46 (0%)	0	0/46 (0%)	0	0/6 (0%)	0	1/82 (1.2%)	1
Infections and infestations
Gastroenteritis	0/46 (0%)	0	1/46 (2.2%)	1	0/6 (0%)	0	0/82 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/46 (0%)	0	0/46 (0%)	0	0/6 (0%)	0	1/82 (1.2%)	1
Pulmonary Embolism	0/46 (0%)	0	0/46 (0%)	0	0/6 (0%)	0	1/82 (1.2%)	1
Surgical and medical procedures
Tracheostomy	0/46 (0%)	0	1/46 (2.2%)	1	0/6 (0%)	0	0/82 (0%)	0
Other (Not Including Serious) Adverse Events
	Controlled Phase - Icatibant (Randomized)		Controlled Phase -Placebo (Randomized)		Controlled Phase - Icatibant (Open Label)		Open Label Extension - Icatibant (Open Label)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/46 (17.4%)		12/46 (26.1%)		0/6 (0%)		23/82 (28%)
Congenital, familial and genetic disorders
Hereditary angioedema	5/46 (10.9%)	5	9/46 (19.6%)	9	0/6 (0%)	0	11/82 (13.4%)	17
Infections and infestations
Upper Respiratory Tract Infection	0/46 (0%)	0	0/46 (0%)	0	0/6 (0%)	0	5/82 (6.1%)	7
Nervous system disorders
Headache	3/46 (6.5%)	4	3/46 (6.5%)	3	0/6 (0%)	0	9/82 (11%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Shire's agreements with investigators vary. All agreements provide Shire the right to embargo communications regarding trial results prior to public release for a period ≤180 days from the time submitted to Shire for review. Shire does not prohibit publication, but can require the removal of confidential information (excluding trial results) and can request postponement of a single-center publication until after disclosure of the trial's multi-center publication.