Angioneurotic Edema, Genetic Disorders, Hereditary Angioedema
Conditions
Brief summary
Hereditary angioedema (HAE) is a genetic disorder characterized by sudden recurrent attacks of local swelling (angioedema). These attacks are often painful and disabling, and, in some cases, life-threatening. HAE is caused by mutations in the C1INH gene that leads to a decrease in the blood level of functional C1INH. This multi-center study was designed to assess the safety and tolerability, efficacy and pharmacodynamics/ pharmacokinetics of recombinant human C1 inhibitor (rhC1INH) in the treatment of acute hereditary angioedema attacks.
Detailed description
A prospectively planned interim analysis will be performed on the double-blind data.
Interventions
DRUGPlacebo
IV
Sponsors
Pharming Technologies B.V.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clear clinical and laboratory diagnosis of HAE * Baseline plasma level of functional C1INH of less than 50% of normal * Evidence for exacerbation or development of a severe abdominal, oro-facial/ pharyngeal/ laryngeal, genito-urinary and/or peripheral HAE attack
Exclusion criteria
* Acquired angioedema * Pregnancy or breastfeeding * Participation in another clinical study within prior 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Beginning of Relief of Symptoms | up to 48 hours after study drug administration | The time to beginning of relief of symptoms has been assessed by using a patient-reported visual analogue scale (VAS) ranging from 0 mm (no symptoms at all) to 100 mm (extremely disabling). Time to beginning of relief of symptoms at the location that showed first VAS score decrease of at least 20 mm from baseline score (t= 0 min) to the next assessment time-point). Assessment time-points were taken on pre-scheduled time-points after drug administration: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to beginning of relief has been calculated as median time, by using the exact time-points on which each assessment was performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Minimal Symptoms | up to 48 hours after study drug administration | the time to minimal symptoms was the time to minimal symptoms for an attack, assessed using the Visual Analogue Scale (VAS) score. Symptoms were said to be minimal when the VAS score at all locations was below 20 mm. Assessment time-points were: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to minimal symptoms has been calculated by using the exact time-points on which each assessment was performed. |
Countries
Netherlands, Romania
Participant flow
Recruitment details
During the double-blind phase of the study, patients were randomized once to receive 100 IU/kg rhC1INH or Saline in a ratio of 1:1. After conclusion of the double-blind phase, patients with subsequent eligible attacks could be treated with open-label 1 vial (2100 IU) of rhC1INH.
Pre-assignment details
Patients could be enrolled into the open-label phase of the study after conclusion of the double-blind phase.
Participants by arm
| Arm | Count |
|---|---|
| 100 IU/kg rhC1INH Includes all subjects randomized who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. | 16 |
| Saline Includes all subjects randomized and who received Saline solution in the double-blind phase. | 16 |
| 1 Vial (2100 IU) rhC1INH Includes all subjects who received 1 vial (2100 IU) open-label rhC1INH in the open-label extension phase. | 43 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Phase | Lost to Follow-up | 1 | 0 | 0 |
| Double-blind Phase | worsening of HAE symptoms | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | 100 IU/kg rhC1INH | Saline | 1 Vial (2100 IU) rhC1INH | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 9 Participants | 11 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 12 Participants | 33 Participants | 58 Participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 28 Participants | 45 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 16 | 5 / 16 | 6 / 57 |
| serious Total, serious adverse events | 0 / 16 | 2 / 16 | 0 / 57 |
Outcome results
Primary
Time to Beginning of Relief of Symptoms
The time to beginning of relief of symptoms has been assessed by using a patient-reported visual analogue scale (VAS) ranging from 0 mm (no symptoms at all) to 100 mm (extremely disabling). Time to beginning of relief of symptoms at the location that showed first VAS score decrease of at least 20 mm from baseline score (t= 0 min) to the next assessment time-point). Assessment time-points were taken on pre-scheduled time-points after drug administration: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to beginning of relief has been calculated as median time, by using the exact time-points on which each assessment was performed.
Time frame: up to 48 hours after study drug administration
Population: The full analysis set (FAS or mITT) was defined as the set of patients who provided Informed Consent, were randomized and took at least one dose of the study drug administration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 100 IU/kg rhC1INH | Time to Beginning of Relief of Symptoms | 62 minutes |
| Saline | Time to Beginning of Relief of Symptoms | 508 minutes |
| 1 Vial (2100 IU) rhC1INH | Time to Beginning of Relief of Symptoms | 61 minutes |
p-value: 0.003Log Rank
Secondary
Time to Minimal Symptoms
the time to minimal symptoms was the time to minimal symptoms for an attack, assessed using the Visual Analogue Scale (VAS) score. Symptoms were said to be minimal when the VAS score at all locations was below 20 mm. Assessment time-points were: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to minimal symptoms has been calculated by using the exact time-points on which each assessment was performed.
Time frame: up to 48 hours after study drug administration
Population: The full analysis set (FAS or mITT) was defined as the set of patients who provided Informed Consent, were randomized and took at least one dose of study drug administration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 100 IU/kg rhC1INH | Time to Minimal Symptoms | 480 minutes |
| Saline | Time to Minimal Symptoms | 1440 minutes |
| 1 Vial (2100 IU) rhC1INH | Time to Minimal Symptoms | 241 minutes |
p-value: 0.005Log Rank