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Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema

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ClinicalTrials.gov Identifier: NCT00097695
Recruitment Status : Completed
First Posted : November 29, 2004
Results First Posted : December 24, 2013
Last Update Posted : June 5, 2014
Sponsor:
Information provided by (Responsible Party):
Shire

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Single Group Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Angioedema
Interventions Drug: Icatibant
Drug: Placebo
Enrollment 84
Recruitment Details  
Pre-assignment Details Patients must have an eligible HAE attack to be randomized.64 patients were in the controlled phase(27icatibant,29 placebo,8subjects with laryngeal attacks were treated with open label icatibant).A total of 72 were treated in the open label phase(20 entered directly into the OLE phase+ 52 from the controlled phase).
Arm/Group Title Randomized -Icatibant Randomized -Placebo Controlled Open-label / Laryngeal Attack Untreated Patients at the Baseline
Hide Arm/Group Description Patients who were randomized to icatibant in the controlled phase after they had an eligible first in-study attack. Patients who were randomized to placebo 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.
Period Title: The Controlled Phase
Started 27 29 8 20
Completed 23 26 3 0 [1]
Not Completed 4 3 5 20
[1]
Patients screened and found eligible but did not have HAE attack or attack was not severe enough
Period Title: The Open Label Extension (OLE) Phase
Started 23 26 3 20
Completed 10 11 1 15
Not Completed 13 15 2 5
Arm/Group Title Randomized -Icatibant Randomized -Placebo Controlled Open-label / Laryngeal Attack Untreated Patients at the Baseline Total
Hide Arm/Group Description Patients who were randomized to icatibant in the controlled phase after they had an eligible first in-study attack. Patients who were randomized to placebo in the controlled phase after they had an eligible first in-study attack. patients who received first treatment Open-Label due to laryngeal symptoms 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. Total of all reporting groups
Overall Number of Baseline Participants 27 29 8 20 84
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 27 participants 29 participants 8 participants 20 participants 84 participants
34.8  (9.81) 34.9  (11.37) 47.1  (13.86) 37.4  (11.48) 36.6  (11.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 27 participants 29 participants 8 participants 20 participants 84 participants
Female
16
  59.3%
21
  72.4%
5
  62.5%
15
  75.0%
57
  67.9%
Male
11
  40.7%
8
  27.6%
3
  37.5%
5
  25.0%
27
  32.1%
1.Primary Outcome
Title Time to Onset of Symptom Relief (TOSR)
Hide Description

The primary efficacy endpoint was TOSR assessed by the patient using a Visual Analogue Scale (VAS). The VAS is a scale used to measure intensity of each symptom of the attack at baseline and at the pre-determined time points throughout treatment period. It consists of a horizontal 10cm line, with the 0 point corresponding to a state where patient experiences no symptoms at all and the 10cm point represents the worst symptoms ever experienced by patient. The patient indicates his/her current state of symptoms by drawing a mark across the horizontal line.

TOSR was defined as the time between time of injection to time of first documented onset of symptom relief for the 3 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 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Time to onset of symptom relief - Controlled phase - ITT population (patients experiencing moderate to very severe acute cutaneous and/or abdominal HAE attacks)
Arm/Group Title Randomized -Icatibant Randomized -Placebo
Hide Arm/Group Description:
27 Patients were randomized to icatibant in the controlled phase after they had an eligible first in-study attack.
29 Patients were randomized to placebo in the controlled phase after they had an eligible first in-study attack.
Overall Number of Participants Analyzed 27 29
Median (Inter-Quartile Range)
Unit of Measure: Hours
2.5
(1.1 to 6.0)
4.6
(1.8 to 10.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomized -Icatibant, Randomized -Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.142
Comments [Not Specified]
Method Wilcoxon version of the log-rank test
Comments The Wilcoxon version of the log-rank test of SAS was used to calculate statistical significance between p- vs icatibant group and placebo group.
2.Secondary Outcome
Title Time to Regression (Start of Improvement) According to Patient
Hide Description This parameter assessed the time to regression (start of improvement) of observable(visible) symptoms according to the patients. Patients were asked "Report date and time when you feel that your symptoms start to improve".
Time Frame 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Randomized -Icatibant Randomized -Placebo
Hide Arm/Group Description:
27 Patients were randomized to icatibant in the controlled phase after they had an eligible first in-study attack.
29 Patients were randomized to placebo in the controlled phase after they had an eligible first in-study attack.
Overall Number of Participants Analyzed 27 29
Median (Inter-Quartile Range)
Unit of Measure: Hours
0.8
(0.5 to 2.0)
16.9 [1] 
(3.2 to NA)
[1]
14 patients were censored in the placebo group; these patients were censored as no data for time to regression (start of improvement) according to the patient were documented within the observation period.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomized -Icatibant, Randomized -Placebo
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 Wilcoxon version of the log-rank test
Comments The median time to onset is calculated using Kaplan-Meier methodology. The Wilcoxon version of the log-rank test of SAS is used.
3.Secondary Outcome
Title Time to Almost Complete Symptom Relief
Hide Description The time to almost complete symptom relief was defined as a score between 0 and 10 mm on the VAS for at least 3 consecutive measurements for all symptom.
Time Frame 5 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Randomized Control Trial-icatibant Randomized Control Trial-placebo
Hide Arm/Group Description:
27 Patients were randomized to icatibant in the controlled phase after they had an eligible first in-study attack.
29 Patients were randomized to placebo in the controlled phase after they had an eligible first in-study attack.
Overall Number of Participants Analyzed 27 29
Median (Inter-Quartile Range)
Unit of Measure: Hours
8.5
(2.5 to 31.5)
19.4
(10.2 to 55.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Randomized Control Trial-icatibant, Randomized Control Trial-placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value = 0.079
Comments [Not Specified]
Method Wilcoxon version of the log-rank test
Comments The median time to almost complete symptom relief was calculated using Kaplan-Meier methodology.The Wilcoxon version of the log-rank test of SAS used.
Time Frame An AE was assigned to the controlled phase if the event start date was between the first treatment of the first attack and the first treatment in the OLE phase.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Controlled Phase- Icatibant (Randomized Subjects ) Controlled Phase- Placebo (Randomized Subjects Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) Open Label Extension Phase- Icatibant (Previously Randomized) Open Label Extension -Icatibant (Subjects w/ Laryngeal Attack) Open Label Extension Phase(Untreated Patients at the Baseline)
Hide Arm/Group Description Patients who were randomized to icatibant in the controlled and experienced adverse events while participating in the controlled phase. Patients who were randomized to 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 or 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. 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- Placebo (Randomized Subjects Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) Open Label Extension Phase- Icatibant (Previously Randomized) Open Label Extension -Icatibant (Subjects w/ Laryngeal Attack) Open Label Extension Phase(Untreated Patients at the Baseline)
Affected / at Risk (%) Affected / at Risk (%) 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 Subjects ) Controlled Phase- Placebo (Randomized Subjects Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) Open Label Extension Phase- Icatibant (Previously Randomized) Open Label Extension -Icatibant (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   0/27 (0.00%)      0/29 (0.00%)      1/8 (12.50%)      3/49 (6.12%)      0/3 (0.00%)      0/20 (0.00%)    
Congenital, familial and genetic disorders             
HAE attack  1  0/27 (0.00%)  0 0/29 (0.00%)  0 1/8 (12.50%)  1 1/49 (2.04%)  1 0/3 (0.00%)  0 0/20 (0.00%)  0
Gastrointestinal disorders             
Pancreatitis  2  0/27 (0.00%)  0 0/29 (0.00%)  0 0/8 (0.00%)  0 1/49 (2.04%)  1 0/3 (0.00%)  0 0/20 (0.00%)  0
General disorders             
Chest Pain  2  0/27 (0.00%)  0 0/29 (0.00%)  0 0/8 (0.00%)  0 1/49 (2.04%)  1 0/3 (0.00%)  0 0/20 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, Hereditary Angioedem
2
Term from vocabulary, MedDRA 8.1
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 Subjects ) Controlled Phase- Placebo (Randomized Subjects Controlled Phase- Icatibant (Subjects w/ Laryngeal Attack) Open Label Extension Phase- Icatibant (Previously Randomized) Open Label Extension -Icatibant (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   12/27 (44.44%)      19/29 (65.52%)      6/8 (75.00%)      39/49 (79.59%)      3/3 (100.00%)      17/20 (85.00%)    
Congenital, familial and genetic disorders             
Hereditary angioedema  1 [1]  4/27 (14.81%)  5/29 (17.24%)  4/8 (50.00%)  17/49 (34.69%)  1/3 (33.33%)  5/20 (25.00%) 
Gastrointestinal disorders             
Nausea  1  0/27 (0.00%)  3/29 (10.34%)  0/8 (0.00%)  2/49 (4.08%)  0/3 (0.00%)  0/20 (0.00%) 
General disorders             
Administration site conditions  1  3/27 (11.11%)  4/29 (13.79%)  0/8 (0.00%)  11/49 (22.45%)  1/3 (33.33%)  3/20 (15.00%) 
Infections and infestations             
Infections  1  4/27 (14.81%)  4/29 (13.79%)  1/8 (12.50%)  20/49 (40.82%)  0/3 (0.00%)  7/20 (35.00%) 
Injury, poisoning and procedural complications             
Contusion  1  0/27 (0.00%)  0/29 (0.00%)  0/8 (0.00%)  3/49 (6.12%)  0/3 (0.00%)  0/20 (0.00%) 
Investigations             
Dizziness  1  2/27 (7.41%)  1/29 (3.45%)  0/8 (0.00%)  0/49 (0.00%)  1/3 (33.33%)  0/20 (0.00%) 
Blood Creatine Phosphokinase Increased  1  1/27 (3.70%)  0/29 (0.00%)  0/8 (0.00%)  1/49 (2.04%)  1/3 (33.33%)  2/20 (10.00%) 
Nervous system disorders             
Headache/Migraine  1  0/27 (0.00%)  2/29 (6.90%)  2/8 (25.00%)  0/49 (0.00%)  2/3 (66.67%)  1/20 (5.00%) 
Respiratory, thoracic and mediastinal disorders             
Nasal Congestion  1  2/27 (7.41%)  0/29 (0.00%)  0/8 (0.00%)  0/49 (0.00%)  0/3 (0.00%)  0/20 (0.00%) 
Skin and subcutaneous tissue disorders             
Pruritus  1  0/27 (0.00%)  2/29 (6.90%)  0/8 (0.00%)  0/49 (0.00%)  0/3 (0.00%)  0/20 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 8.1
[1]
HAE attacks were over-reported as AEs as some investigators reported new attacks as AEs in addition to worsening of attacks in Icatibant treated patients.
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.
Results Point of Contact
Name/Title: Alan Kimura, MD, PhD
Organization: Shire Human Genetic Therapies, Inc.
Phone: 781-482-0738
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT00097695     History of Changes
Other Study ID Numbers: JE049 #2103
FAST1 ( Other Identifier: Shire HGT )
First Submitted: November 26, 2004
First Posted: November 29, 2004
Results First Submitted: January 24, 2011
Results First Posted: December 24, 2013
Last Update Posted: June 5, 2014