Trial Outcomes & Findings for Observational Safety Study for KALBITOR (Ecallantide) in the Treatment of Acute Attacks of Hereditary Angioedema (NCT NCT01059526)

NCT ID: NCT01059526

Last Updated: 2021-06-08

Results Overview

Based on medical review of multiple preferred terms for treatment emergent adverse events (TEAEs) suggestive of Type 1 hypersensitivity; terms included adverse drug reaction, anaphylaxis, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, erythema, flushing, hot flush, pharyngeal edema, laryngeal edema, pruritus, pruritus generalized, rash, rash erythematous, rhinitis allergic, rhinorrhea, throat irritation, urticaria, urticaria localized, dyspnea, and wheezing. Records of patients with any of these TEAE referred terms were reviewed further to assess potential hypersensitivity reactions, considering factors such as timing of TEAEs in relationship to dose (ie, occurred within 24 hours after start of KALBITOR treatment), accompanying symptoms, Investigator causality assessment (ie, reported as possibly, probably, or definitely related to study drug), and any other available clinical information. Anaphylaxis subset determined based on criteria established by the NIAID.

• Recruitment status: COMPLETED
• Target enrollment: 81 participants
• Primary outcome timeframe: 12 months after first treatment
• Results posted on: 2021-06-08

Participant Flow

Patients indicated in the US FDA-approved product label for KALBITOR (ecallantide) who experienced an acute attack of HAE were eligible for inclusion in this trial.

Subjects were to complete screening/enrollment procedures on a separate day prior to receiving KALBITOR treatment for an acute attack of HAE. The primary and secondary endpoints were analyzed for the Safety population only (all patients who received at least 1 treatment dose of KALBITOR).

Participant milestones

Measure	Patients Naive to KALBITOR HAE patients that have not been treated with KALBITOR (ecallantide) prior to enrollment in the study ecallantide: 30 mg SC	Patients Non- Naive to KALBITOR HAE patients that have been treated with KALBITOR prior to enrollment in the study ecallantide: 30 mg SC
Overall Study STARTED	41	40
Overall Study Treated	21	23
Overall Study COMPLETED	11	18
Overall Study NOT COMPLETED	30	22

Reasons for withdrawal

Measure	Patients Naive to KALBITOR HAE patients that have not been treated with KALBITOR (ecallantide) prior to enrollment in the study ecallantide: 30 mg SC	Patients Non- Naive to KALBITOR HAE patients that have been treated with KALBITOR prior to enrollment in the study ecallantide: 30 mg SC
Overall Study Patient enrolled but not treated	20	17
Overall Study Adverse Event	2	2
Overall Study Protocol Violation	0	1
Overall Study Withdrawal by Subject	3	1
Overall Study Lost to Follow-up	4	1
Overall Study Patient found to be dermatographic	1	0

Baseline Characteristics

Observational Safety Study for KALBITOR (Ecallantide) in the Treatment of Acute Attacks of Hereditary Angioedema

Baseline characteristics by cohort

Measure	Patients Naive to KALBITOR n=21 Participants HAE patients that have not been treated with KALBITOR (ecallantide) prior to enrollment in the study ecallantide: 30 mg SC	Patients Non- Naive to KALBITOR n=23 Participants HAE patients that have been treated with KALBITOR prior to enrollment in the study ecallantide: 30 mg SC	Total n=44 Participants Total of all reporting groups
Age, Continuous	48.2 years STANDARD_DEVIATION 16.09 • n=5 Participants	38.3 years STANDARD_DEVIATION 14.86 • n=7 Participants	43.0 years STANDARD_DEVIATION 16.08 • n=5 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	15 Participants n=7 Participants	30 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	20 Participants n=5 Participants	22 Participants n=7 Participants	42 Participants n=5 Participants
Race/Ethnicity, Customized Black	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: 12 months after first treatment

Population: Safety population; defined as all patients who received at least 1 treatment dose of KALBITOR

Based on medical review of multiple preferred terms for treatment emergent adverse events (TEAEs) suggestive of Type 1 hypersensitivity; terms included adverse drug reaction, anaphylaxis, anaphylactic reaction, anaphylactoid reaction, hypersensitivity, erythema, flushing, hot flush, pharyngeal edema, laryngeal edema, pruritus, pruritus generalized, rash, rash erythematous, rhinitis allergic, rhinorrhea, throat irritation, urticaria, urticaria localized, dyspnea, and wheezing. Records of patients with any of these TEAE referred terms were reviewed further to assess potential hypersensitivity reactions, considering factors such as timing of TEAEs in relationship to dose (ie, occurred within 24 hours after start of KALBITOR treatment), accompanying symptoms, Investigator causality assessment (ie, reported as possibly, probably, or definitely related to study drug), and any other available clinical information. Anaphylaxis subset determined based on criteria established by the NIAID.

Outcome measures

Measure	Safety Population n=44 Participants Safety population; defined as all patients who received at least 1 treatment dose of KALBITOR	Patients Non- Naive to KALBITOR HAE patients that have been treated with KALBITOR prior to enrollment in the study ecallantide: 30 mg SC
Occurrence of Anaphylaxis or Other Adverse Events Suggestive of Hypersensitivity Type 1 hypersensitivity	4 participants Interval 0.6 to 17.6	—
Occurrence of Anaphylaxis or Other Adverse Events Suggestive of Hypersensitivity Anaphylaxis per NIAID criteria	2 participants Interval 0.0 to 10.7	—

PRIMARY outcome

Timeframe: 12 months after first treatment

Population: Based on total number of patients who were not positive for the antibody class at study entry and had at least one post-baseline antibody evaluation. N=40 evaluable patients for all immunoglobulin antibody classes; N=41 evaluable patients for IgE to ecallantide antibodies; N=41 evaluable patients for neutralizing antibodies to ecallantide.

Seroconversion is the development of detectable specific antibodies in the blood serum. Serum was tested for development of antibodies (irrespective of immunoglobulin class) against ecallantide at screening and at all safety evaluations. Positive results were to undergo a confirmatory test. Confirmed positive samples were further titered. Patients who developed an antibody response were evaluated for the development of neutralizing antibodies. Patients also had their serum analyzed for IgE-specific antibodies to ecallantide at screening and during safety evaluations. Positive results underwent a confirmatory test. Confirmed positive samples were further titered.

Outcome measures

Measure	Safety Population n=41 Participants Safety population; defined as all patients who received at least 1 treatment dose of KALBITOR	Patients Non- Naive to KALBITOR HAE patients that have been treated with KALBITOR prior to enrollment in the study ecallantide: 30 mg SC
Occurrence of Seroconversion to Anti-ecallantide Antibodies Upon Exposure to KALBITOR. Seroconversion based on all Ig antibody classes	6 participants Interval 3.9 to 26.1	—
Occurrence of Seroconversion to Anti-ecallantide Antibodies Upon Exposure to KALBITOR. Seroconversion based on IgE to ecallantide	0 participants NA = 95% CI is not evaluable for 0 events	—
Occurrence of Seroconversion to Anti-ecallantide Antibodies Upon Exposure to KALBITOR. Seroconversion based on neutralizing antibodies	5 participants Interval 2.2 to 22.2	—

PRIMARY outcome

Timeframe: 12 months after first treatment

Events of ecchymosis, hemorrhage, petechiae, spontaneous hemorrhage, hematoma, gastrointestinal bleeding, hemorrhagic stroke and any other term indicative of a bleeding event or increased tendency for bleeding were reviewed to determine the occurrence of hypocoagulability. Events of clotting, thrombosis, pulmonary embolism, vaso-occlusive stroke, myocardial infarction, and any other term indicative of a clotting event or increased risk of clotting were reviewed to determine the occurrence of hypercoagulability.

Outcome measures

Measure	Safety Population n=44 Participants Safety population; defined as all patients who received at least 1 treatment dose of KALBITOR	Patients Non- Naive to KALBITOR HAE patients that have been treated with KALBITOR prior to enrollment in the study ecallantide: 30 mg SC
Occurrence of Adverse Events Related to Disordered Coagulation (Hypercoagulability and Hypocoagulability) Upon Exposure to KALBITOR	0 participants NA = 95% CI is not evaluable for 0 events	—

SECONDARY outcome

Timeframe: within 4 hours post dose

Population: Safety population; defined as all patients who received at least 1 treatment dose of KALBITOR. Analysis only includes episodes of patients who were treated at the study site.

The Overall Response Assessment was to be completed every 30 minutes after treatment until patient discharge. Patients evaluated their response to treatment as "a lot better or resolved," "a little better," "the same," "a little worse," or "a lot worse." The data presented is based on the best response achieved following a single dose of KALBITOR (Dose A) for the first HAE treatment episode. Responses of "a lot better or resolved" and "a little better" were combined to form a category of "Better." Similarly, "a little worse" and "a lot worse" were combined to form a category of "Worse." Patients treated in a clinic (study site) could have been discharged after an hour and hence may have only had 2 post-treatment evaluations (30 and 60 minutes); response assessments may not have been consistently provided when patients were treated at an alternate site outside of the study site.

Outcome measures

Measure	Safety Population n=11 Participants Safety population; defined as all patients who received at least 1 treatment dose of KALBITOR	Patients Non- Naive to KALBITOR n=17 Participants HAE patients that have been treated with KALBITOR prior to enrollment in the study ecallantide: 30 mg SC
Overall Patient Response Assessment Better	10 participants	15 participants
Overall Patient Response Assessment Same	1 participants	2 participants
Overall Patient Response Assessment Worse	0 participants	0 participants

Adverse Events

Safety Population

Serious events: 6 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Measure	Safety Population n=44 participants at risk Safety population; defined as all patients who received at least 1 treatment dose of KALBITOR
Metabolism and nutrition disorders Dehydration	4.5% 2/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
Congenital, familial and genetic disorders Hereditary angioedema	4.5% 2/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
General disorders Drug ineffective for unapproved indication	2.3% 1/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
Immune system disorders Anaphylactic reaction	2.3% 1/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
Skin and subcutaneous tissue disorders Erythema	2.3% 1/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.

Other adverse events

Measure	Safety Population n=44 participants at risk Safety population; defined as all patients who received at least 1 treatment dose of KALBITOR
Investigations Skin test positive	11.4% 5/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
Congenital, familial and genetic disorders Hereditary angioedema	9.1% 4/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
Gastrointestinal disorders Abdominal pain upper	4.5% 2/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
Gastrointestinal disorders Nausea	4.5% 2/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
Infections and infestations Upper respiratory tract infection	4.5% 2/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
Metabolism and nutrition disorders Dehydration	4.5% 2/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.
Skin and subcutaneous tissue disorders Erythema	4.5% 2/44 • 12 months after first treatment Adverse events were to be recorded for the duration of the study. Results are presented for episode-based treatment-emergent adverse events--ie, those that occurred or worsened in severity within 24 hours after the start of treatment with KALBITOR, or were reported as related to treatment with KALBITOR regardless of time of onset post treatment.

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER