Angioedema
Conditions
Keywords
Hereditary Angioedema, C1 inhibitor deficiency, HAE, Icatibant, Bradykinin antagonist, acute attack, subcutaneous
Brief summary
The purpose of this study is to assess the efficacy and safety of Icatibant, a bradykinin antagonist in the treatment of acute cutaneous and/or abdominal attacks in patients with hereditary angioedema (HAE).
Detailed description
This Phase II/III study consisted of two parts: A controlled phase and An Open label extension(OLE) phase. The controlled phase describes the double blind part of the study and was intended to evaluate the efficacy of icatibant in decreasing the time to onset of symptom relief compared with placebo for the first treated cutaneous and/or abdominal attack in randomised patients. Patients experienced a laryngeal attack were not randomised, but treated with open label icatibant according to the controlled phase procedures and assessments. The outcome of this group was to be reported descriptively. After treatment of the first attack in the controlled phase, the patients were eligible to enter the OLE phase. In the OLE phase, patients who experienced angioedema attacks severe enough to warrant treatment were to be treated with s.c. icatibant as appropriate until the end of the study.The OLE phase became a modified open label extension where all 56 patients who had been randomised and the last randomised patient had concluded the double-blind phase. The modified open label extension period permitted treatment for 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 double blind phase was still ongoing.
Interventions
DRUGIcatibant
30 mg (3mL) subcutaneous icatibant injection in the abdominal region
DRUGPlacebo
Solution for injection, matched to study drug Single dose: 3 mL
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
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 complement 1 esterase inhibitor \[C1-INH\] deficiency); * Current edema be in the cutaneous, abdominal and/or laryngeal areas; * Current edema be moderate to severe according to the investigator's Symptom Score.
Exclusion criteria
* Diagnosis of angioedema other than HAE, for example, acquired angioedema (AAE); * 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 edema attack; * Treatment with replacement therapy, including C1-INH products (e.g. human C1-INH preparations), less than 3 days from onset of the current edema attack; * Treatment with ACE inhibitors (e.g. Lotensin, Prinivil, Accupril); * Evidence of severe, symptomatic coronary artery disease based on medical history or screening examination; * Serious concomitant illnesses that the physician considers to be a contraindication for participation in the trial; * Pregnancy and/or breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Symptom Relief (TOSR) | 5 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Regression (Start of Improvement) According to Patient | 5 days | 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 to Almost Complete Symptom Relief | 5 days | 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. |
Countries
United States
Participant flow
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).
Participants by arm
| Arm | Count |
|---|---|
| Randomized -Icatibant Patients who were randomized to icatibant in the controlled phase after they had an eligible first in-study attack. | 27 |
| Randomized -Placebo Patients who were randomized to placebo in the controlled phase after they had an eligible first in-study attack. | 29 |
| Controlled Open-label / Laryngeal Attack patients who received first treatment Open-Label due to laryngeal symptoms | 8 |
| 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. | 20 |
| Total | 84 |
Baseline characteristics
| Characteristic | Randomized -Icatibant | Randomized -Placebo | Controlled Open-label / Laryngeal Attack | Untreated Patients at the Baseline | Total |
|---|---|---|---|---|---|
| Age, Continuous | 34.8 Years STANDARD_DEVIATION 9.81 | 34.9 Years STANDARD_DEVIATION 11.37 | 47.1 Years STANDARD_DEVIATION 13.86 | 37.4 Years STANDARD_DEVIATION 11.48 | 36.6 Years STANDARD_DEVIATION 11.5 |
| Sex: Female, Male Female | 16 Participants | 21 Participants | 5 Participants | 15 Participants | 57 Participants |
| Sex: Female, Male Male | 11 Participants | 8 Participants | 3 Participants | 5 Participants | 27 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 | 12 / 27 | 19 / 29 | 6 / 8 | 39 / 49 | 3 / 3 | 17 / 20 |
| serious Total, serious adverse events | 0 / 27 | 0 / 29 | 1 / 8 | 3 / 49 | 0 / 3 | 0 / 20 |
Outcome results
Primary
Time to Onset of Symptom Relief (TOSR)
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
Population: Time to onset of symptom relief - Controlled phase - ITT population (patients experiencing moderate to very severe acute cutaneous and/or abdominal HAE attacks)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized -Icatibant | Time to Onset of Symptom Relief (TOSR) | 2.5 Hours |
| Randomized -Placebo | Time to Onset of Symptom Relief (TOSR) | 4.6 Hours |
p-value: 0.142Wilcoxon version of the log-rank test
Secondary
Time to Almost Complete Symptom Relief
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized -Icatibant | Time to Almost Complete Symptom Relief | 8.5 Hours |
| Randomized -Placebo | Time to Almost Complete Symptom Relief | 19.4 Hours |
p-value: =0.079Wilcoxon version of the log-rank test
Secondary
Time to Regression (Start of Improvement) According to Patient
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized -Icatibant | Time to Regression (Start of Improvement) According to Patient | 0.8 Hours |
| Randomized -Placebo | Time to Regression (Start of Improvement) According to Patient | 16.9 Hours |
p-value: <0.001Wilcoxon version of the log-rank test