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

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ClinicalTrials.gov Identifier: NCT00912093

Recruitment Status : Completed

First Posted : June 3, 2009

Results First Posted : August 6, 2014

Last Update Posted : September 22, 2014

Sponsor:

Information provided by (Responsible Party):

Shire

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Hereditary Angioedema
Interventions	Drug: Icatibant Drug: Placebo
Enrollment	98

Participant Flow

Recruitment Details
Pre-assignment Details


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 cu...	Subjects with moderate to severe cu...	Subjects with mild to moderate lary...	Subjects with mild to moderate lary...	Subjects with severe (post-amendmen...
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
Reason Not Completed
Death	0	1	0	0	0
Medical Condition	0	1	0	0	0
Lost to Follow-up	0	0	0	0	1
Period Title: The Open Label Extension (OLE) 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 cu...	Subjects with moderate to severe cu...	Subjects with mild to moderate lary...	Subjects with mild to moderate lary...	Subjects with severe (post-amendmen...	Total of all reporting groups
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 Number of Baseline Participants		43	45	3	2	5	98
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	43 participants	45 participants	3 participants	2 participants	5 participants	98 participants
		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 Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	43 participants	45 participants	3 participants	2 participants	5 participants	98 participants
	Female	27 62.8%	29 64.4%	2 66.7%	1 50.0%	2 40.0%	61 62.2%
	Male	16 37.2%	16 35.6%	1 33.3%	1 50.0%	3 60.0%	37 37.8%
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	43 participants	45 participants	3 participants	2 participants	5 participants	98 participants
American Indian or Alaska Native		0	0	0	0	0	0
Asian		0	0	0	0	0	0
Black or African American		3	0	0	0	0	3
Native Hawaiian or Other Pacific		0	0	0	0	0	0
White		38	40	3	2	4	87
Other		2	5	0	0	1	8
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	43 participants	45 participants	3 participants	2 participants	5 participants	98 participants
United States		26	32	2	2	3	65
Hungary		3	1	0	0	0	4
Canada		1	0	0	0	0	1
Ukraine		0	1	0	0	0	1
Romania		3	1	1	0	0	5
Australia		2	3	0	0	0	5
Russian Federation		2	1	0	0	0	3
South Africa		2	1	0	0	1	4
Israel		4	5	0	0	1	10
Weight (kg) Measure Type: Number Unit of measure: Participants	Number Analyzed	43 participants	45 participants	3 participants	2 participants	5 participants	98 participants
<= 50 kg		4	2	0	0	0	6
>50-75 kg		16	20	1	2	0	39
>75-100 kg		14	13	1	0	3	31
>100 kg		9	10	1	0	2	22

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 adminis...
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 cu...	Subjects with moderate to severe cu...
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
Overall Number of Participants Analyzed	43	45
Median (95% Confidence Interval) Unit of Measure: Hours
	2.0 (1.5 to 3.0)	19.8 (6.1 to 26.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Peto-Peto Wilcoxon
	Comments	[Not Specified]

2.Secondary Outcome


Title	Time to Onset of Primary Symptom Relief
Description	Time to primary symptom relief was calculated from the time of study d...
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


Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal
Arm/Group Description:	Subjects with moderate to severe cu...	Subjects with moderate to severe cu...
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
Overall Number of Participants Analyzed	43	45
Median (95% Confidence Interval) Unit of Measure: Hours
	1.5 (1.0 to 2.0)	18.5 (3.6 to 23.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Peto-Peto Wilcoxon
	Comments	[Not Specified]

3.Secondary Outcome


Title	Time to Almost Complete Symptom Relief
Description	Time to almost complete symptom relief was calculated from the time of...
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


Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal
Arm/Group Description:	Subjects with moderate to severe cu...	Subjects with moderate to severe cu...
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
Overall Number of Participants Analyzed	43	45
Median (95% Confidence Interval) Unit of Measure: Hours
	8.0 (5.0 to 42.5)	36.0 (29.0 to 50.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.012
	Comments	[Not Specified]
	Method	Peto Peto Wilcoxon
	Comments	[Not Specified]

4.Secondary Outcome


Title	Time to Subject-Assessed Initial Symptom Improvement
Description	Time to initial symptom improvement was calculated from the time of st...
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


Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal
Arm/Group Description:	Subjects with moderate to severe cu...	Subjects with moderate to severe cu...
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
Overall Number of Participants Analyzed	43	45
Median (95% Confidence Interval) Unit of Measure: Hours
	0.8 (0.5 to 1.0)	3.5 (1.9 to 5.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Peto-Peto Wilcoxon
	Comments	[Not Specified]

5.Secondary Outcome


Title	Time to Investigator-Assessed Initial Symptom Improvement
Description	Time to initial symptom improvement was calculated from the time of st...
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


Arm/Group Title	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal	Randomized-Placebo (Blinded Treatment)-Non-laryngeal
Arm/Group Description:	Subjects with moderate to severe cu...	Subjects with moderate to severe cu...
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
Overall Number of Participants Analyzed	43	45
Median (95% Confidence Interval) Unit of Measure: Hours
	0.8 (0.6 to 1.3)	3.4 (2.6 to 6.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized-Icatibant (Blinded Treatment)--Non-laryngeal, Randomized-Placebo (Blinded Treatment)-Non-laryngeal
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Peto-Peto Wilcoxon
	Comments	[Not Specified]

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 tre...		Subjects who were randomized to tre...		Subjects who were not randomized an...		Subjects who treated with icatibant...
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 (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--		--/--
Serious Adverse Events 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 (0.00%)		5/46 (10.87%)		0/6 (0.00%)		7/82 (8.54%)
Cardiac disorders
Myocardial infarction	0/46 (0.00%)	0	1/46 (2.17%)	1	0/6 (0.00%)	0	0/82 (0.00%)	0
Arrhythmia	0/46 (0.00%)	0	0/46 (0.00%)	0	0/6 (0.00%)	0	1/82 (1.22%)	1
Congenital, familial and genetic disorders
Hereditary angioedema	0/46 (0.00%)	0	2/46 (4.35%)	2	0/6 (0.00%)	0	3/82 (3.66%)	3
General disorders
Non-Cardiac Chest Pain	0/46 (0.00%)	0	0/46 (0.00%)	0	0/6 (0.00%)	0	1/82 (1.22%)	1
Hepatobiliary disorders
Cholecystitis	0/46 (0.00%)	0	0/46 (0.00%)	0	0/6 (0.00%)	0	1/82 (1.22%)	1
Infections and infestations
Gastroenteritis	0/46 (0.00%)	0	1/46 (2.17%)	1	0/6 (0.00%)	0	0/82 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/46 (0.00%)	0	0/46 (0.00%)	0	0/6 (0.00%)	0	1/82 (1.22%)	1
Pulmonary Embolism	0/46 (0.00%)	0	0/46 (0.00%)	0	0/6 (0.00%)	0	1/82 (1.22%)	1
Surgical and medical procedures
Tracheostomy	0/46 (0.00%)	0	1/46 (2.17%)	1	0/6 (0.00%)	0	0/82 (0.00%)	0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	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 (17.39%)		12/46 (26.09%)		0/6 (0.00%)		23/82 (28.05%)
Congenital, familial and genetic disorders
Hereditary angioedema	5/46 (10.87%)	5	9/46 (19.57%)	9	0/6 (0.00%)	0	11/82 (13.41%)	17
Infections and infestations
Upper Respiratory Tract Infection	0/46 (0.00%)	0	0/46 (0.00%)	0	0/6 (0.00%)	0	5/82 (6.10%)	7
Nervous system disorders
Headache	3/46 (6.52%)	4	3/46 (6.52%)	3	0/6 (0.00%)	0	9/82 (10.98%)	12

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

Name/Title: Alan Kimura, MD, PhD

Organization: Shire

Phone: 1-617-482-0738

EMail: akimura@shire.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lumry WR, Farkas H, Moldovan D, Toubi E, Baptista J, Craig T, Riedl M. Icatibant for Multiple Hereditary Angioedema Attacks across the Controlled and Open-Label Extension Phases of FAST-3. Int Arch Allergy Immunol. 2015;168(1):44-55. doi: 10.1159/000441060. Epub 2015 Nov 11.

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.

Responsible Party:	Shire
ClinicalTrials.gov Identifier:	NCT00912093 History of Changes
Other Study ID Numbers:	HGT-FIR-054 2009-015606-19 ( EudraCT Number )
First Submitted:	June 2, 2009
First Posted:	June 3, 2009
Results First Submitted:	July 11, 2014
Results First Posted:	August 6, 2014
Last Update Posted:	September 22, 2014

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