Hereditary Angioedema
Conditions
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
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.
Interventions
DRUGIcatibant
Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.
DRUGTranexamic 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.
DRUGOral Placebo
hard capsule matched to tranexamic acid
DRUGS.C. Placebo
solution for injection, matched to icatibant for injection
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Italy
Participant flow
Pre-assignment details
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
Participants by arm
| Arm | Count |
|---|---|
| Randomized Controlled -Icatibant 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. | 36 |
| Randomized Controlled-Tranexamic Acid 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. | 38 |
| 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. | 3 |
| 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 | 8 |
| Total | 85 |
Baseline characteristics
| Characteristic | Randomized Controlled -Icatibant | Total | Untreated Patients at the Baseline | Controlled Open-label / Laryngeal Attack | Randomized Controlled-Tranexamic Acid |
|---|---|---|---|---|---|
| Age, Continuous | 40.4 years STANDARD_DEVIATION 13.59 | 40.9 years STANDARD_DEVIATION 12.8 | 40.6 years STANDARD_DEVIATION 13.51 | 35.0 years STANDARD_DEVIATION 11.36 | 41.9 years STANDARD_DEVIATION 12.36 |
| Region of Enrollment Austria | 3 Participants | 8 Participants | 1 Participants | 0 Participants | 4 Participants |
| Region of Enrollment France | 3 Participants | 6 Participants | 2 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Germany | 13 Participants | 25 Participants | 0 Participants | 0 Participants | 12 Participants |
| Region of Enrollment Hungary | 3 Participants | 6 Participants | 0 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Ireland | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Israel | 4 Participants | 15 Participants | 4 Participants | 3 Participants | 4 Participants |
| Region of Enrollment Italy | 3 Participants | 9 Participants | 1 Participants | 0 Participants | 5 Participants |
| Region of Enrollment Lithuania | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Poland | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Sweden | 3 Participants | 5 Participants | 0 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Switzerland | 2 Participants | 4 Participants | 0 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 24 Participants | 55 Participants | 7 Participants | 1 Participants | 23 Participants |
| Sex: Female, Male Male | 12 Participants | 30 Participants | 1 Participants | 2 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 36 | 16 / 38 | 1 / 3 | 31 / 44 | 1 / 2 | 4 / 8 |
| serious Total, serious adverse events | 4 / 36 | 1 / 38 | 1 / 3 | 9 / 44 | 1 / 2 | 0 / 8 |
Outcome results
Primary
Time to Onset of Symptom Relief.
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Controlled -Icatibant | Time to Onset of Symptom Relief. | 2.0 Hours |
| Randomized Controlled-Tranexamic Acid | Time to Onset of Symptom Relief. | 12.0 Hours |
p-value: <0.00195% CI: [1.901, 6.355]The Wilcoxon version of the log rank
Secondary
Time to Almost Complete Symptom Relief
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Controlled -Icatibant | Time to Almost Complete Symptom Relief | 10.0 Hours |
| Randomized Controlled-Tranexamic Acid | Time to Almost Complete Symptom Relief | 51.0 Hours |
p-value: <0.001The Wilcoxon version of the log rank