FAST2: Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema (HAE)

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00500656
• Collaborator: (none)
• Enrollment: 85
• Location: 1
• Arms: 4
• Actual Duration (Months): 16.8
• Patients Per Site Per Month: 5.1

Study Details

Study Description

Brief Summary

Primary Outcome Measures:

The primary endpoint was the time to onset of symptom relief of the first attack in the double blind phase. H0: λ icatibant/λ tranexamic acid =1 versus H1: λ icatibant/λ tranexamic acid ≠1 Where: λ icatibant refers to the hazard rate under icatibant and λ tranexamic acid refers to the hazard rate under tranexamic acid.

Secondary Outcome Measures:

• Additional efficacy assessments (Time to Almost Complete Symptom Relief)

• Safety and tolerability

• Pharmacoeconomics

Condition or Disease	Intervention/Treatment	Phase
Hereditary Angioedema	Drug: Icatibant; Drug: Tranexamic Acid; Drug: Oral Placebo; Drug: S.C. Placebo	Phase 3

Detailed Description

This was a Phase III, randomised, double blind, double dummy, multicentre, controlled,parallel group study of a 30 mg s.c. formulation of icatibant for the treatment of patients with moderate to very severe symptoms of cutaneous and/or abdominal symptoms of HAE.

The study consisted of two parts: controlled phase and OLE phase. For the primary endpoint, Efficacy was determined by evaluating the differences in study outcomes using a Visual Analogue Scale for patients treated with icatibant and tranexamic acid.

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Randomised Double Blind, Controlled, Parallel Group, Multicentre Study of a Subcutaneous Formulation of Icatibant Versus Oral Tranexamic Acid for the Treatment of Hereditary Angioedema (HAE)
• Actual Study Start Date: Mar 1, 2005
• Actual Primary Completion Date: Jul 25, 2006
• Actual Study Completion Date: Jul 25, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Randomized controlled -Icatibant Subjects received S.C icatibant+ oral placebo Icatibant Form: solution for injection, 3 mL, 10 mg/mL Single dose: 30 mg (3 mL) Placebo Form: hard capsule Single dose: 2 capsules Frequency: 3 x 2 capsules for 2 days, taken orally, 6 to 8 hours apart	Drug: Icatibant; Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.; Other Names: Brand name, Firazyr® ; Drug: Oral Placebo; hard capsule matched to tranexamic acid; Other Names: Placebo
Active Comparator: Randomized controlled-Tranexamic acid Subjects received oral Tranexamic acid+ S.C. placebo Tranexamic acid Form: over encapsulated film tablet Single dose: 1000 mg (2 capsules) Frequency: 3 x 2 capsules for 2 days, taken orally, 6 to 8 hours apart Placebo Form: solution for injection, matched to icatibant for injection Single dose: 3 mL Frequency: one subcutaneous injection in the abdominal region	Drug: Tranexamic Acid; over encapsulated film tablet an anti-fibrinolytic agent,is used in some European countries for the treatment of acute oedema episodes and the continuous prophylaxis of HAE.; Drug: S.C. Placebo; solution for injection, matched to icatibant for injection; Other Names: Placebo
Experimental: Controlled Open-label / laryngeal attack Patients with laryngeal symptoms at the baseline were not randomised but treated with icatibant open label during the controlled phase.	Drug: Icatibant; Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.; Other Names: Brand name, Firazyr®
Experimental: Untreated patients at the baseline Patients who were screened and found eligible but did not experience an angioedema attack, or had an attack that was not severe enough to merit treatment while the controlled phase was ongoing were treated in the open label phase with icatibant	Drug: Icatibant; Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.; Other Names: Brand name, Firazyr®

Outcome Measures

Primary Outcome Measures

1. Time to Onset of Symptom Relief. [2 days]

   The primary efficacy endpoint was Time to onset of symptom relief (TOSR) following treatment with either icatibant or tranexamic acid. The median time to onset of symptom relief for the icatibant group was compared to the the median time to onset of symptom relief for the tranexamic acid group. TOSR was defined as the time between time of injection to time of first documented onset of symptom relief for the three primary symptoms: cutaneous swelling, cutaneous skin, and abdominal pain. The primary symptom was based on the type of attack. For abdominal attacks, the single primary symptom was abdominal pain. For cutaneous attacks, the single primary symptom was either skin swelling or skin pain, whichever was most severe.

Secondary Outcome Measures

1. Time to Almost Complete Symptom Relief [48 hours]

   Almost complete symptom relief was defined as a score between 0 and 10 mm on the VAS for at least three consecutive measurements for all symptoms.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age above 18 years;

• Documented diagnosis of HAE Type I or II (confirmed C1-INH deficiency);

• Current edema in the cutaneous, abdominal and/or laryngeal areas;

• Current edema moderate to severe according to the investigator's Symptom Score.

Exclusion Criteria:

• Diagnosis of angioedema other than HAE,

• Participation in a clinical trial of another investigational medicinal product (IMP)within the past month

• Treatment with any pain medication since onset of the current angioedema attack

• Treatment with replacement therapy, including C1-INH products, less than 3 days before onset of the current angioedema attack

• Treatment with Tranexamic acid replacement therapy within a week before onset of the current angioedema attack

• Treatment with ACE inhibitors

• Contraindications for Tranexamic acid

• Evidence of coronary artery disease based on medical history or Screening examination in particular unstable angina pectoris or severe coronary heart disease

• Congestive heart failure (class 3 and 4)

• Serum creatinine level of ≥ 250 μmol/L

• Serious concomitant illness that the investigator considered to be a contraindication for participation in the trial

• Pregnancy (as assessed prior to treatment) and/or breast-feeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Università degli Studi di Milano, Dipartimento di Medicina Interna	Milano		Italy	20123

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: NCT00500656
• Other Study ID Numbers: JE049 #2102; 2004-001540-71
• First Posted: Jul 13, 2007
• Last Update Posted: Jun 9, 2021
• Last Verified: May 1, 2021

• Additional relevant MeSH terms: Angioedema; Angioedemas, Hereditary; Icatibant; Tranexamic Acid

Study Results

Participant Flow

Pre-assignment Detail	85 patients participated in the study(36 in the icatibant group and 38 in the tranexamic acid group)3 patients with laryngeal symptoms at Baseline.8 Patients were screened and found eligible but did not experience an angioedema attack, or had an attack that was not severe enough to merit treatment while the controlled phase was ongoing

Arm/Group Title	Randomized Controlled -Icatibant	Randomized Controlled-Tranexamic Acid	Controlled Open-label / Laryngeal Attack	Untreated Patients at the Baseline
Arm/Group Description	Patients who were randomized to icatibant + Oral placebo (hard capsule matched to tranexamic acid) in the controlled phase after they had an eligible first in-study attack.	Patients who were randomized to received oral Tranexamic acid + S.C. placebo(solution for injection, matched to icatibant for injection) in the controlled phase after they had an eligible first in-study attack.	Patients with laryngeal symptoms at the baseline were not randomised but treated with icatibant open label during the controlled phase.	Patients who were screened and found eligible but did not experience an angioedema attack, or had an attack that was not severe enough to merit treatment while the controlled phase was ongoing were treated in the open label phase with icatibant
Period Title: Controlled Phase
STARTED	36	38	3	8
COMPLETED	26	28	2	0
NOT COMPLETED	10	10	1	8
Period Title: Controlled Phase
STARTED	23	21	2	8
COMPLETED	16	9	1	6
NOT COMPLETED	7	12	1	2

Baseline Characteristics

Arm/Group Title	Randomized Controlled -Icatibant	Randomized Controlled-Tranexamic Acid	Controlled Open-label / Laryngeal Attack	Untreated Patients at the Baseline	Total
Arm/Group Description	Patients who were randomized to icatibant + Oral placebo (hard capsule matched to tranexamic acid) in the controlled phase after they had an eligible first in-study attack.	Patients who were randomized to received oral Tranexamic acid + S.C. placebo(solution for injection, matched to icatibant for injection) in the controlled phase after they had an eligible first in-study attack.	Patients with laryngeal symptoms at the baseline were not randomised but treated with icatibant open label during the controlled phase.	Patients who were screened and found eligible but did not experience an angioedema attack, or had an attack that was not severe enough to merit treatment while the controlled phase was ongoing were treated in the open label phase with icatibant	Total of all reporting groups
Overall Participants	36	38	3	8	85
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.4 (13.59)	41.9 (12.36)	35.0 (11.36)	40.6 (13.51)	40.9 (12.8)
Sex: Female, Male (Count of Participants)
Female	24 66.7%	23 60.5%	1 33.3%	7 87.5%	55 64.7%
Male	12 33.3%	15 39.5%	2 66.7%	1 12.5%	30 35.3%
Region of Enrollment (Count of Participants)
Austria	3 8.3%	4 10.5%	0 0%	1 12.5%	8 9.4%
France	3 8.3%	1 2.6%	0 0%	2 25%	6 7.1%
Germany	13 36.1%	12 31.6%	0 0%	0 0%	25 29.4%
Hungary	3 8.3%	3 7.9%	0 0%	0 0%	6 7.1%
Ireland	0 0%	1 2.6%	0 0%	0 0%	1 1.2%
Israel	4 11.1%	4 10.5%	3 100%	4 50%	15 17.6%
Italy	3 8.3%	5 13.2%	0 0%	1 12.5%	9 10.6%
Lithuania	1 2.8%	2 5.3%	0 0%	0 0%	3 3.5%
Poland	1 2.8%	2 5.3%	0 0%	0 0%	3 3.5%
Sweden	3 8.3%	2 5.3%	0 0%	0 0%	5 5.9%
Switzerland	2 5.6%	2 5.3%	0 0%	0 0%	4 4.7%

Outcome Measures

1. Primary Outcome

Title	Time to Onset of Symptom Relief.
Description	The primary efficacy endpoint was Time to onset of symptom relief (TOSR) following treatment with either icatibant or tranexamic acid. The median time to onset of symptom relief for the icatibant group was compared to the the median time to onset of symptom relief for the tranexamic acid group. TOSR was defined as the time between time of injection to time of first documented onset of symptom relief for the three primary symptoms: cutaneous swelling, cutaneous skin, and abdominal pain. The primary symptom was based on the type of attack. For abdominal attacks, the single primary symptom was abdominal pain. For cutaneous attacks, the single primary symptom was either skin swelling or skin pain, whichever was most severe.
Time Frame	2 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Randomized Controlled -Icatibant	Randomized Controlled-Tranexamic Acid
Arm/Group Description	Patients who were randomized to icatibant + Oral placebo (hard capsule matched to tranexamic acid) in the controlled phase after they had an eligible first in-study attack.	Patients who were randomized to received oral Tranexamic acid + S.C. placebo(solution for injection, matched to icatibant for injection) in the controlled phase after they had an eligible first in-study attack.
Measure Participants	36	38
Median (Inter-Quartile Range) [Hours]	2.0	12.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized Controlled -Icatibant, Randomized Controlled-Tranexamic Acid
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	The Wilcoxon version of the log rank
	Comments	The median time to onset was calculated using Kaplan Meier methodology. The Wilcoxon version of the log rank test of SAS was used
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.475
	Confidence Interval	(2-Sided) 95%; 1.901 to 6.355
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to Almost Complete Symptom Relief
Description	Almost complete symptom relief was defined as a score between 0 and 10 mm on the VAS for at least three consecutive measurements for all symptoms.
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Randomized Controlled -Icatibant	Randomized Controlled-Tranexamic Acid
Arm/Group Description	Patients who were randomized to icatibant + Oral placebo (hard capsule matched to tranexamic acid) in the controlled phase after they had an eligible first in-study attack.	Patients who were randomized to received oral Tranexamic acid + S.C. placebo(solution for injection, matched to icatibant for injection) in the controlled phase after they had an eligible first in-study attack.
Measure Participants	36	38
Median (Inter-Quartile Range) [Hours]	10.0	51.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized Controlled -Icatibant, Randomized Controlled-Tranexamic Acid
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	The Wilcoxon version of the log rank
	Comments	The median time to almost complete symptom relief was calculated using Kaplan Meier methodology.The Wilcoxon version of the log rank test SAS was used

Adverse Events

Time Frame	An AE was assigned to the controlled phase if the start date of the event was between the first treatment of the first attack and the first treatment in the OLE phase.
Arm/Group Title	Controlled Phase- Icatibant (Randomized Subjects )		Controlled Phase- Tranexamic Acid (Randomized Subjects)		Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack)		Open Label Extension Phase- Icatibant (Previously Randomized)		Open Label Extension Phase (Subjects w/ Laryngeal Attack)		Open Label Extension Phase(Untreated Patients at the Baseline
Arm/Group Description	Patients who were randomized to icatibant+ oral placebo in the controlled phase and experienced adverse events while participating in the controlled phase		Patients who were randomized to Tranexamic acid+ S.C. placebo in the controlled phase and experienced adverse events while participating in the controlled phase.		This represents adverse events during the controlled phase that were experienced by Patients with laryngeal symptoms at the baseline and were treated with open label icatibant during the controlled phase.		Patients who were randomized to either icatibant+ oral placebo or Tranexamic acid+ S.C. placebo in the controlled phase and experienced adverse events while participating in the open label extension phase.		This represents adverse events during the open label extension phase that were experienced by Patients with laryngeal symptoms at the baseline and got treated with open label icatibant during the controlled phase and Open label extension phase.		This represents adverse events experienced by Patients who were screened and found eligible but did not experience an angioedema attack, or had an attack that was not severe enough to merit treatment while the controlled phase was ongoing.
All Cause Mortality
	Controlled Phase- Icatibant (Randomized Subjects )		Controlled Phase- Tranexamic Acid (Randomized Subjects)		Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack)		Open Label Extension Phase- Icatibant (Previously Randomized)		Open Label Extension Phase (Subjects w/ Laryngeal Attack)		Open Label Extension Phase(Untreated Patients at the Baseline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Controlled Phase- Icatibant (Randomized Subjects )		Controlled Phase- Tranexamic Acid (Randomized Subjects)		Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack)		Open Label Extension Phase- Icatibant (Previously Randomized)		Open Label Extension Phase (Subjects w/ Laryngeal Attack)		Open Label Extension Phase(Untreated Patients at the Baseline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/36 (11.1%)		1/38 (2.6%)		1/3 (33.3%)		9/44 (20.5%)		1/2 (50%)		0/8 (0%)
Cardiac disorders
Aortic Value Sclerosis	0/36 (0%)		1/38 (2.6%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		0/8 (0%)
Coronary Artery Disease	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Congenital, familial and genetic disorders
Hereditary Angioedema	2/36 (5.6%)		0/38 (0%)		1/3 (33.3%)		3/44 (6.8%)		1/2 (50%)		0/8 (0%)
General disorders
Sudden Cardiac Death	0/36 (0%)		1/38 (2.6%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		0/8 (0%)
Hepatobiliary disorders
Cholelithiasis	1/36 (2.8%)		0/38 (0%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		0/8 (0%)
Infections and infestations
Cystitis	1/36 (2.8%)		0/38 (0%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		0/8 (0%)
Gastroenteritis	1/36 (2.8%)		0/38 (0%)		0/3 (0%)		2/44 (4.5%)		0/2 (0%)		0/8 (0%)
Urinary Track Infection Bacterial	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Injury, poisoning and procedural complications
Head Injury	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Road Traffic Accident	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Wound	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Investigations
Pancreatic Enzymes Increased	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix Carcinoma Stage 0	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Psychiatric disorders
Suicide Attempt	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Renal and urinary disorders
Renal Failure	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Surgical and medical procedures
Tooth Extraction	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Vascular disorders
Hypertensive Crisis	1/36 (2.8%)		0/38 (0%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Controlled Phase- Icatibant (Randomized Subjects )		Controlled Phase- Tranexamic Acid (Randomized Subjects)		Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack)		Open Label Extension Phase- Icatibant (Previously Randomized)		Open Label Extension Phase (Subjects w/ Laryngeal Attack)		Open Label Extension Phase(Untreated Patients at the Baseline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/36 (52.8%)		16/38 (42.1%)		1/3 (33.3%)		31/44 (70.5%)		1/2 (50%)		4/8 (50%)
Blood and lymphatic system disorders
Blood and Lymphatic system disorders	0/36 (0%)		2/38 (5.3%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Congenital, familial and genetic disorders
Hereditary Angioedema	10/36 (27.8%)		6/38 (15.8%)		1/3 (33.3%)		10/44 (22.7%)		1/2 (50%)		1/8 (12.5%)
General disorders
Injection Site Reaction	2/36 (5.6%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		0/8 (0%)
Infections and infestations
Nasopharyngitis	2/36 (5.6%)		3/38 (7.9%)		0/3 (0%)		4/44 (9.1%)		0/2 (0%)		0/8 (0%)
Pharyngitis	0/36 (0%)		1/38 (2.6%)		0/3 (0%)		3/44 (6.8%)		0/2 (0%)		0/8 (0%)
Urinary Track Infection	0/36 (0%)		0/38 (0%)		0/3 (0%)		6/44 (13.6%)		0/2 (0%)		0/8 (0%)
Gingival Infection	0/36 (0%)		0/38 (0%)		0/3 (0%)		0/44 (0%)		1/2 (50%)		0/8 (0%)
Dental Caries	0/36 (0%)		0/38 (0%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		1/8 (12.5%)
Respiratory Track Infection	0/36 (0%)		0/38 (0%)		0/3 (0%)		1/44 (2.3%)		0/2 (0%)		1/8 (12.5%)
Injury, poisoning and procedural complications
Injury, poisoning and procedual complications	3/36 (8.3%)		1/38 (2.6%)		0/3 (0%)		3/44 (6.8%)		0/2 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders	2/36 (5.6%)		1/38 (2.6%)		0/3 (0%)		3/44 (6.8%)		0/2 (0%)		0/8 (0%)
Nervous system disorders
Headache	2/36 (5.6%)		2/38 (5.3%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		0/8 (0%)
Dizziness	0/36 (0%)		0/38 (0%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		1/8 (12.5%)
Skin and subcutaneous tissue disorders
Pruritus	0/36 (0%)		0/38 (0%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		1/8 (12.5%)
Surgical and medical procedures
Dental Operation	0/36 (0%)		0/38 (0%)		0/3 (0%)		0/44 (0%)		0/2 (0%)		1/8 (12.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.