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Efficacy Study of DX-88 (Ecallantide) to Treat Acute Attacks of Hereditary Angioedema (HAE)

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ClinicalTrials.gov Identifier: NCT00457015
Recruitment Status : Completed
First Posted : April 5, 2007
Results First Posted : May 4, 2010
Last Update Posted : February 20, 2018
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 (HAE)
Interventions Drug: ecallantide
Drug: Phosphate Buffer Saline (PBS), pH 7.0
Enrollment 96
Recruitment Details  
Pre-assignment Details Patients were screened in advance of presenting with an HAE attack but were randomized only upon attack.
Arm/Group Title KALBITOR (Ecallantide) Placebo
Hide Arm/Group Description KALBITOR (ecallantide, DX-88) 30 mg given as three 10 mg/mL subcutaneous injections. Placebo, Phosphate Buffer Saline (PBS), pH 7.0 given as 3 subcutaneous injections.
Period Title: Overall Study
Started 48 48
Completed 48 47
Not Completed 0 1
Reason Not Completed
Left study site against medical advice             0             1
Arm/Group Title KALBITOR (Ecallantide) Placebo Total
Hide Arm/Group Description KALBITOR (ecallantide, DX-88) 30 mg given as three 10 mg/mL subcutaneous injections. Placebo, Phosphate Buffer Saline (PBS), pH 7.0 given as 3 subcutaneous injections. Total of all reporting groups
Overall Number of Baseline Participants 48 48 96
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 48 participants 48 participants 96 participants
37.0  (13.12) 38.0  (12.19) 37.5  (12.61)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 48 participants 48 participants 96 participants
Female
37
  77.1%
28
  58.3%
65
  67.7%
Male
11
  22.9%
20
  41.7%
31
  32.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 48 participants 48 participants 96 participants
United States 47 48 95
Canada 1 0 1
Symptom Complexes at Baseline   [1] 
Measure Type: Number
Unit of measure:  Symptom complexes
Number Analyzed 48 participants 48 participants 96 participants
Internal Head/Neck 8 13 21
Stomach/GI 18 27 45
Genital/Buttocks 6 5 11
External Head/Neck 14 9 23
Cutaneous 34 21 55
[1]
Measure Description: More than one baseline symptom complex could be reported per patient; hence the number of complexes is greater than the number of patients in each group. Patient were to have at least one symptom complex that was moderate or severe. The total number of symptom complexes was 155.
1.Primary Outcome
Title Change From Baseline in Mean Symptom Complex Severity (MSCS) Score at 4 Hours Post-dose
Hide Description The Mean Symptom Complex Severity (MSCS) score is a validated, comprehensive point-in-time measure of symptom severity. At baseline and 4 hours, patients rated the severity on a categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe) for symptoms at each affected anatomical location. Ratings were averaged to obtain the MSCS score. A decrease in MSCS score reflected an improvement in symptoms; clinically meaningful improvement was indicated by a reduction in the score of 0.30 or more.
Time Frame baseline, 4 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Patients were excluded from the analysis if they did not have data for the endpoint being analyzed. Reasons for patients being excluded are for ecallantide: 1 patient treated for severe upper airway compromise; for placebo: 3 patient treated for severe upper airway compromise and 3 patients with missing 4-hour data. Best score=0.0; worst score=3.0.
Arm/Group Title KALBITOR (Ecallantide) Placebo
Hide Arm/Group Description:
KALBITOR (ecallantide, DX-88) 30 mg given as three 10 mg/mL subcutaneous injections.
Placebo, Phosphate Buffer Saline (PBS), pH 7.0 given as 3 subcutaneous injections.
Overall Number of Participants Analyzed 47 42
Mean (Standard Deviation)
Unit of Measure: units on a scale
MSCS Score at baseline 2.2  (0.50) 2.0  (0.35)
MSCS Score at 4 hours post-dose 1.4  (0.75) 1.6  (0.77)
Change from baseline in MSCS at 4 hours post-dose -0.8  (0.63) -0.4  (0.82)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection KALBITOR (Ecallantide), Placebo
Comments The primary efficacy analysis compared the change from baseline in MSCS Score at 4 hours post-dosing for patients treated with ecallantide and placebo. Treatment effect was assessed by the nonparametric Blocked Wilcoxon Rank Sum test because of an assumed non-normal distribution.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.010
Comments No adjustment was made for multiple comparisons. Treatment effect will be deemed statistically significant if the coefficient for the treatment group within the statistical model is significant at level 0.05.
Method Blocked Wilcoxon rank sum test
Comments [Not Specified]
2.Secondary Outcome
Title Treatment Outcome Score at 4 Hours Post-Dose
Hide Description Treatment Outcome Score (TOS) is a validated, comprehensive measure of symptom response to treatment. At 4 hours , patient assessment of response characterized by their change from baseline in symptom severity and collected by anatomic site of attack involvement, was recorded on a categorical scale (significant improvement [100; best value]to significant worsening [-100; worst value]). Clinically meaningful improvement was indicated by a TOS of 30 or higher.
Time Frame 4 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Patients were excluded from this analysis if they did not have data for the endpoint being analyzed. The reasons for patients being excluded from this analysis are for ecallantide: 1 patient treated for severe upper airway compromise and for placebo: 3 patient treated for severe upper airway compromise and 3 patients with missing 4-hour data.
Arm/Group Title KALBITOR (Ecallantide) Placebo
Hide Arm/Group Description:
KALBITOR (ecallantide, DX-88) 30 mg given as three 10 mg/mL subcutaneous injections.
Placebo, Phosphate Buffer Saline (PBS), pH 7.0 given as 3 subcutaneous injections.
Overall Number of Participants Analyzed 47 42
Mean (Standard Deviation)
Unit of Measure: units on a scale
53.4  (49.70) 8.1  (63.18)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection KALBITOR (Ecallantide), Placebo
Comments The analysis compared the TOS at 4 hours post-dosing for patients treated with ecallantide and placebo. Treatment effect was assessed by the nonparametric Blocked Wilcoxon Rank Sum test because of an assumed non-normal distribution.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments No adjustment was made for multiple comparisons. Treatment effect will be deemed statistically significant if the coefficient for the treatment group within the statistical model is significant at level 0.05.
Method Blocked Wilcoxon rank sum test
Comments [Not Specified]
3.Secondary Outcome
Title Patients With Significant Improvement in Overall Response
Hide Description Patients were to be asked to perform an overall response assessment at intervals during the first 4 hours post-dose. Assessments were to be made relative to baseline (ie, immediately before initial dosing) using a 5-category scale. Categories were: significant improvement = "a lot better or resolved"; improvement = "a little better"; same = response unchanged; worsening = "a little worse"; significant worsening = "a lot worse". Significant improvement is the first time that a patient responded to the overall response assessment as "a lot better or resolved."
Time Frame 4 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
The time to significant improvement is not provided in this display as the estimated median times were not reached by 240 minutes. Instead, the number of patients with significant improvement is provided per treatment arm.
Arm/Group Title KALBITOR (Ecallantide) Placebo
Hide Arm/Group Description:
KALBITOR (ecallantide, DX-88) 30 mg given as three 10 mg/mL subcutaneous injections.
Placebo, Phosphate Buffer Saline (PBS), pH 7.0 given as 3 subcutaneous injections.
Overall Number of Participants Analyzed 48 48
Measure Type: Number
Unit of Measure: participants
22 12
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection KALBITOR (Ecallantide), Placebo
Comments Kaplan-Meier analysis using the Log-Rank test was used to compare the time distribution between the 2 treatment groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.102
Comments No adjustment was made for multiple comparisons. Treatment effect will be deemed statistically significant if the coefficient for the treatment group within the statistical model is significant at level 0.05.
Method Log Rank
Comments [Not Specified]
4.Secondary Outcome
Title Patients With a Successful Response at 4 Hours Post-dosing, Based on the Change From Baseline in the MSCS Score
Hide Description A successful response was defined as improvement in existing laryngeal symptom complex,stabilization of an existing peripheral symptom complex, or a change from baseline in the MSCS score at 4 hours of at least -1.0.
Time Frame baseline, 4 hours post-dosing
Hide Outcome Measure Data
Hide Analysis Population Description
Diary information was not available for 1 patient in the placebo arm. This patient was considered not evaluable and excluded from the analysis.
Arm/Group Title KALBITOR (Ecallantide) Placebo
Hide Arm/Group Description:
KALBITOR (ecallantide, DX-88) 30 mg given as three 10 mg/mL subcutaneous injections.
Placebo, Phosphate Buffer Saline (PBS), pH 7.0 given as 3 subcutaneous injections.
Overall Number of Participants Analyzed 48 47
Measure Type: Number
Unit of Measure: participants
45 28
5.Secondary Outcome
Title Proportion of Patients Maintaining a Significant Improvement in Overall Response Through 24 Hours
Hide Description Maintenance of significant improvement was defined as achieving and maintaining a significant improvement in overall response through 24 hours after dosing. Patient response categories were: significant improvement = "a lot better or resolved"; improvement = "a little better"; same = response unchanged; worsening = "a little worse"; significant worsening = "a lot worse".
Time Frame 24 hours post-dosing
Hide Outcome Measure Data
Hide Analysis Population Description
Diary information was not available for 1 patient in the placebo arm. This patient was considered not evaluable and excluded from the analysis.
Arm/Group Title KALBITOR (Ecallantide) Placebo
Hide Arm/Group Description:
KALBITOR (ecallantide, DX-88) 30 mg given as three 10 mg/mL subcutaneous injections.
Placebo, Phosphate Buffer Saline (PBS), pH 7.0 given as 3 subcutaneous injections.
Overall Number of Participants Analyzed 48 47
Measure Type: Number
Unit of Measure: participants
21 10
Time Frame up to 7 days post-dose
Adverse Event Reporting Description For patients that were given an open-label dose of ecallantide for severe upper airway compromise or failed or incomplete response, or relapse, all adverse events occurring prior to open-label dosing are included in the following tables where all patients are presented in the double-blind, randomized treatment groups.
 
Arm/Group Title KALBITOR (Ecallantide) Placebo
Hide Arm/Group Description KALBITOR (ecallantide, DX-88) 30 mg given as three 10 mg/mL subcutaneous injections. Placebo, Phosphate Buffer Saline (PBS), pH 7.0 given as 3 subcutaneous injections.
All-Cause Mortality
KALBITOR (Ecallantide) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
KALBITOR (Ecallantide) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/48 (0.00%)   3/48 (6.25%) 
Congenital, familial and genetic disorders     
Hereditary angioedema  1  0/48 (0.00%)  3/48 (6.25%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 10.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
KALBITOR (Ecallantide) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   5/48 (10.42%)   9/48 (18.75%) 
Gastrointestinal disorders     
Diarrhoea  1  0/48 (0.00%)  3/48 (6.25%) 
Nausea  1  3/48 (6.25%)  1/48 (2.08%) 
Vomiting  1  0/48 (0.00%)  3/48 (6.25%) 
Nervous system disorders     
Headache  1  2/48 (4.17%)  5/48 (10.42%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 10.0
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.
Dyax agreements vary, but Dyax will not prohibit any investigator from publishing. Dyax reviews publications prior to public release and can request deferral by up to 60 days beyond the proposed publication date if necessary to preserve its intellectual property. Dyax can request changes to publications to remove non-study-related confidential information. Dyax can also request deferral of single-center publications until after disclosure of the clinical trial's primary publication.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Physician
Organization: Shire Development LLC
Phone: +1 866 842 5335
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT00457015     History of Changes
Other Study ID Numbers: EDEMA4 (DX-88/20)
First Submitted: April 4, 2007
First Posted: April 5, 2007
Results First Submitted: December 30, 2009
Results First Posted: May 4, 2010
Last Update Posted: February 20, 2018