Hereditary Angioedema
Conditions
Keywords
HAE, Type I HAE, Type II HAE
Brief summary
This study is being conducted to evaluate the efficacy and safety of icatibant compared to placebo in patients experiencing acute attacks of hereditary angioedema (HAE).
Detailed description
This Phase 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 and safety of icatibant compared with placebo for the first treated cutaneous and/or abdominal attack. Patients with moderate to severe abdominal or cutaneous attacks were randomized to receive a single, blinded, subcutaneous injection of icatibant (30 mg) or placebo. After a protocol amendment, patients with mild to moderate laryngeal HAE attacks were also randomized to receive a single, blinded subcutaneous injection of icatibant (30 mg) or placebo in order to obtain blinded, controlled efficacy and safety data for this subset of subjects. Patients experiencing severe laryngeal attacks (post-amendment) or mild to severe laryngeal attacks (pre-amendment) were to receive open-label icatibant. After treatment of the first attack in the controlled phase, 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 study was discontinued or the product was commercially available.
Interventions
DRUGIcatibant
Single subcutaneous injection of icatibant, 30 mg
DRUGPlacebo
Single subcutaneous injection of matching placebo
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each patient must meet the following criteria to be enrolled in this study. 1. The patient is ≥18 years old at the time of informed consent. 2. The patient has a documented diagnosis of HAE type I or II. The diagnosis will be confirmed either by documented decreased C4 levels and/or immunogenic or functional C1-INH deficiency results (\<50% of normal levels) consistent with HAE types I and II or by medical history. 3. The current HAE attack must be in the cutaneous, abdominal and/or laryngeal (inclusive of laryngeal and pharyngeal) areas. 4. Cutaneous or abdominal HAE attacks must be moderate to very severe as determined by investigator global assessment at pre-treatment assessments 5. The patient must report at least 1 VAS score ≥ 30mm 6. The patient commences treatment within 6 hours of the attack becoming at least mild (laryngeal) or moderate (non-laryngeal) in severity, but not more than 12 hours after the onset of the attack. 7. Women of childbearing potential must have a negative urine pregnancy test and must use appropriate methods to prevent pregnancy during their participation in the study.
Exclusion criteria
Patients who meet any of the following criteria will be excluded from the study. 1. The patient has a diagnosis of angioedema other than HAE type I or II. 2. The patient has received previous treatment with icatibant. 3. The patient has participated in a clinical trial and has received treatment with another investigational medicinal product within the past 30 days. 4. The patient has received treatment with any pain medication since the onset of the current angioedema attack. 5. The patient has received replacement therapy (fresh frozen plasma \[FFP\], C1-INH products) less than 5 days (120 hours) from the onset of the current angioedema attack. 6. The patient is receiving treatment with angiotensin converting enzyme (ACE) inhibitors. 7. Evidence of coronary artery disease based on medical history or screening examination in particular unstable angina pectoris or severe coronary heart disease; 8. The patient has a serious concomitant illness or condition that, in the opinion of the Investigator, would be a contraindication for participation in the trial. 9. The patient is pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Symptom Relief for an Acute Attack, as Assessed by the Patient | Up to 120 hours post-dose | Time to onset of symptom relief was calculated from study drug administration to onset of symptom relief, where onset of symptom relief was defined as the earliest of 3 consecutive measurements in which there was a 50% reduction from pretreatment in composite VAS score. Composite VAS score comprised 3 symptoms, including skin swelling, skin pain, and abdominal pain, for cutaneous and abdominal attacks and 5 symptoms, including skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice change, for laryngeal attacks. Subjects who did not achieve symptom relief within the observation period were censored at the last observation time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of Primary Symptom Relief | Up to 120 hours post-dose | Time to primary symptom relief was calculated from the time of study drug administration to the onset of primary symptom relief, where onset of primary symptom relief was determined using the subject-assessed VAS score for a single primary symptom (determined by edema location) and defined as the earliest of 3 consecutive non-missing measurements in which a pre-specified reduction from the pretreatment value was met. Subjects who did not achieve primary symptom relief within the observation period were censored at the last observation time. |
| Time to Almost Complete Symptom Relief | Up to 120 Hours post treatment | Time to almost complete symptom relief was calculated from the time of study drug administration to almost complete symptom relief, where almost complete symptom relief was defined as the earliest of 3 consecutive non-missing measurements in which all VAS scores \<10 mm. Subjects who did not achieve almost complete symptom relief within the observation period were censored at the last observation time. |
| Time to Subject-Assessed Initial Symptom Improvement | Up to 120 hours post-dose | Time to initial symptom improvement was calculated from the time of study drug administration to initial symptom improvement as determined by the subject as the time they felt symptoms were starting to improve. Subjects who did not achieve initial symptom improvement within the observation period were censored at the last observation time. |
| Time to Investigator-Assessed Initial Symptom Improvement | Up to 120 hours post-dose | Time to initial symptom improvement was calculated from the time of study drug administration to initial symptom improvement as determined by the investigator as the time they felt symptoms were starting to improve. Subjects who did not achieve initial symptom improvement within the observation period were censored at the last observation time. |
Countries
Australia, Canada, Hungary, Israel, Romania, Russia, South Africa, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Randomized-Icatibant (Blinded Treatment)--Non-laryngeal Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of icatibant 30 mg in the controlled phase | 43 |
| Randomized-Placebo (Blinded Treatment)-Non-laryngeal Subjects with moderate to severe cutaneous or abdominal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase | 45 |
| Randomized-Icatibant (Blinded Treatment)--Laryngeal Subjects with mild to moderate laryngeal attacks of HAE randomized to receive a single subcutaneous injection of icatibant 30 mg in the controlled phase | 3 |
| Randomized-Placebo (Blinded Treatment)-Laryngeal Subjects with mild to moderate laryngeal attacks of HAE randomized to receive a single subcutaneous injection of matching placebo in the controlled phase | 2 |
| Open-Label Icatibant-Severe Laryngeal Subjects with severe (post-amendment) or mild to severe (pre-amendment) laryngeal attacks of HAE treated with subcutaneous injection of icatibant 30 mg in the controlled phase | 5 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| The Controlled Phase | Death | 0 | 1 | 0 | 0 | 0 |
| The Controlled Phase | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| The Controlled Phase | Medical Condition | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Randomized-Icatibant (Blinded Treatment)--Non-laryngeal | Randomized-Placebo (Blinded Treatment)-Non-laryngeal | Randomized-Icatibant (Blinded Treatment)--Laryngeal | Randomized-Placebo (Blinded Treatment)-Laryngeal | Open-Label Icatibant-Severe Laryngeal | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 36.1 years STANDARD_DEVIATION 13.69 | 36.6 years STANDARD_DEVIATION 11.18 | 40.3 years STANDARD_DEVIATION 6.66 | 50.0 years STANDARD_DEVIATION 22.63 | 41.6 years STANDARD_DEVIATION 11.78 | 37.0 years STANDARD_DEVIATION 12.46 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 1 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 38 Participants | 40 Participants | 3 Participants | 2 Participants | 4 Participants | 87 Participants |
| Region of Enrollment Australia | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Region of Enrollment Canada | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Hungary | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Region of Enrollment Israel | 4 Participants | 5 Participants | 0 Participants | 0 Participants | 1 Participants | 10 Participants |
| Region of Enrollment Romania | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 5 Participants |
| Region of Enrollment Russian Federation | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Region of Enrollment South Africa | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Ukraine | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 26 Participants | 32 Participants | 2 Participants | 2 Participants | 3 Participants | 65 Participants |
| Sex: Female, Male Female | 27 Participants | 29 Participants | 2 Participants | 1 Participants | 2 Participants | 61 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 1 Participants | 1 Participants | 3 Participants | 37 Participants |
| Weight (kg) >100 kg | 9 Participants | 10 Participants | 1 Participants | 0 Participants | 2 Participants | 22 Participants |
| Weight (kg) >50-75 kg | 16 Participants | 20 Participants | 1 Participants | 2 Participants | 0 Participants | 39 Participants |
| Weight (kg) <= 50 kg | 4 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants |
| Weight (kg) >75-100 kg | 14 Participants | 13 Participants | 1 Participants | 0 Participants | 3 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 46 | 12 / 46 | 0 / 6 | 23 / 82 |
| serious Total, serious adverse events | 0 / 46 | 5 / 46 | 0 / 6 | 7 / 82 |
Outcome results
Primary
Time to Onset of Symptom Relief for an Acute Attack, as Assessed by the Patient
Time to onset of symptom relief was calculated from study drug administration to onset of symptom relief, where onset of symptom relief was defined as the earliest of 3 consecutive measurements in which there was a 50% reduction from pretreatment in composite VAS score. Composite VAS score comprised 3 symptoms, including skin swelling, skin pain, and abdominal pain, for cutaneous and abdominal attacks and 5 symptoms, including skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice change, for laryngeal attacks. Subjects who did not achieve symptom relief within the observation period were censored at the last observation time.
Time frame: Up to 120 hours post-dose
Population: Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized-Icatibant (Blinded Treatment)--Non-laryngeal | Time to Onset of Symptom Relief for an Acute Attack, as Assessed by the Patient | 2.0 Hours |
| Randomized-Placebo (Blinded Treatment)-Non-laryngeal | Time to Onset of Symptom Relief for an Acute Attack, as Assessed by the Patient | 19.8 Hours |
p-value: <0.001Peto-Peto Wilcoxon
Secondary
Time to Almost Complete Symptom Relief
Time to almost complete symptom relief was calculated from the time of study drug administration to almost complete symptom relief, where almost complete symptom relief was defined as the earliest of 3 consecutive non-missing measurements in which all VAS scores \<10 mm. Subjects who did not achieve almost complete symptom relief within the observation period were censored at the last observation time.
Time frame: Up to 120 Hours post treatment
Population: Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized-Icatibant (Blinded Treatment)--Non-laryngeal | Time to Almost Complete Symptom Relief | 8.0 Hours |
| Randomized-Placebo (Blinded Treatment)-Non-laryngeal | Time to Almost Complete Symptom Relief | 36.0 Hours |
p-value: 0.012Peto Peto Wilcoxon
Secondary
Time to Investigator-Assessed Initial Symptom Improvement
Time to initial symptom improvement was calculated from the time of study drug administration to initial symptom improvement as determined by the investigator as the time they felt symptoms were starting to improve. Subjects who did not achieve initial symptom improvement within the observation period were censored at the last observation time.
Time frame: Up to 120 hours post-dose
Population: Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized-Icatibant (Blinded Treatment)--Non-laryngeal | Time to Investigator-Assessed Initial Symptom Improvement | 0.8 Hours |
| Randomized-Placebo (Blinded Treatment)-Non-laryngeal | Time to Investigator-Assessed Initial Symptom Improvement | 3.4 Hours |
p-value: <0.001Peto-Peto Wilcoxon
Secondary
Time to Onset of Primary Symptom Relief
Time to primary symptom relief was calculated from the time of study drug administration to the onset of primary symptom relief, where onset of primary symptom relief was determined using the subject-assessed VAS score for a single primary symptom (determined by edema location) and defined as the earliest of 3 consecutive non-missing measurements in which a pre-specified reduction from the pretreatment value was met. Subjects who did not achieve primary symptom relief within the observation period were censored at the last observation time.
Time frame: Up to 120 hours post-dose
Population: Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized-Icatibant (Blinded Treatment)--Non-laryngeal | Time to Onset of Primary Symptom Relief | 1.5 Hours |
| Randomized-Placebo (Blinded Treatment)-Non-laryngeal | Time to Onset of Primary Symptom Relief | 18.5 Hours |
p-value: <0.001Peto-Peto Wilcoxon
Secondary
Time to Subject-Assessed Initial Symptom Improvement
Time to initial symptom improvement was calculated from the time of study drug administration to initial symptom improvement as determined by the subject as the time they felt symptoms were starting to improve. Subjects who did not achieve initial symptom improvement within the observation period were censored at the last observation time.
Time frame: Up to 120 hours post-dose
Population: Non-laryngeal Intent-to-Treat (nl-ITT) population included all subjects with non-laryngeal attacks of HAE randomized to treatment. Subjects were analyzed according to the randomized treatment regardless of the treatment actually received. This was the primary analysis population for efficacy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized-Icatibant (Blinded Treatment)--Non-laryngeal | Time to Subject-Assessed Initial Symptom Improvement | 0.8 Hours |
| Randomized-Placebo (Blinded Treatment)-Non-laryngeal | Time to Subject-Assessed Initial Symptom Improvement | 3.5 Hours |
p-value: <0.001Peto-Peto Wilcoxon