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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
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
Hide 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
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
Hide 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
Hide 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
1.Primary Outcome
Title Time to Onset of Symptom Relief for an Acute Attack, as Assessed by the Patient
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Show Statistical Analysis 1 Hide 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]
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)
Hide 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   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide 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
Show Other (Not Including Serious) Adverse Events Hide 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
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
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