Angioneurotic Edema, 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 lead to a decrease in the blood level of functional C1INH. This multi-center study was designed to assess the safety and tolerability, efficacy, and pharmacokinetics/pharmacodynamics of recombinant human C1 inhibitor (rhC1INH) in the treatment of acute hereditary angioedema attacks. Funding Source - FDA OOPD
Detailed description
A prospectively planned interim analysis will be performed on the double-blind data.
Interventions
DRUGplacebo
saline solution
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
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Clear clinical and laboratory diagnosis of HAE * Plasma level of functional C1INH of less than 50% of normal * Acute abdominal, urogenital, peripheral, and/or oro-facial/pharyngeal/laryngeal HAE attack Main
Exclusion criteria
* Acquired angioedema * Pregnancy or breastfeeding * Treatment with any investigational drug within prior 30 days * Body weight \>120 kg
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 at the location that showed the first visual analogue scale (VAS) score decrease of at least 20 mm from baseline score with persistence to the next timepoint, assessment timepoints were taken on pre-scheduled time-points after study drug administration: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours and 48 hours. Time to beginning of relief has been calculated as median time, by using the exact timepoints 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 timepoints were: baseline, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours and 48 hours. Time to minimal symtoms has been calculated by using the exact timepoints on which each assessment was performed. |
Countries
Netherlands
Participant flow
Recruitment details
During the double-blind phase of the study, patients were randomized once to receive 100 IU/kg rhC1INH, 50 IU/kg rhC1INH or Saline in a ratio of 1:1:1. After treatment in the double-blind phase, patients with subsequent eligible attacks could be treated with open-label 50 IU/kg rhC1INH.
Pre-assignment details
Patients could be enrolled into the open-label phase of the study after treatment in the double-blind phase of the study, including those enrolled but not treated in the double-blind phase.
Participants by arm
| Arm | Count |
|---|---|
| 100 IU/kg rhC1INH Baseline characteristics were calculated for the modified intention to treat (mITT) and per protocol analysis populations, which included all subjects who received 100 IU/kg rhC1INH. | 13 |
| 50 IU/kg rhC1INH Baseline characteristics were calculated for the modified intention to treat (mITT) and per protocol analysis populations, which included subjects who received 50 IU/kg rhC1INH. One (1) subject was randomized to the 50 IU/kg rhC1INH arm, but did not receive study drug administration and was excluded from the mITT analysis population. | 12 |
| Placebo Baseline characteristics were calculated for the modified intention to treat (mITT) analysis population, which included all subjects randomized to the placebo arm. | 13 |
| 50 IU/kg Open-label rhC1INH Baseline characteristics were calculated for the modified intention to treat (mITT)analysis population, which included all subjects who received 50 IU/kg open-label rhC1INH. | 39 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Open-label Phase | Lost to Follow-up | 0 | 0 | 0 | 4 |
| Open-label Phase | Withdrawal by Subject | 0 | 0 | 0 | 6 |
Baseline characteristics
| Characteristic | Placebo | 100 IU/kg rhC1INH | 50 IU/kg rhC1INH | 50 IU/kg Open-label rhC1INH | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 0 Participants | 9 Participants | 11 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 11 Participants | 12 Participants | 30 Participants | 65 Participants |
| Sex: Female, Male Female | 12 Participants | 8 Participants | 8 Participants | 22 Participants | 50 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 4 Participants | 17 Participants | 27 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 | 2 / 13 | 2 / 12 | 3 / 13 | 18 / 62 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 | 0 / 13 | 4 / 62 |
Outcome results
Primary
Time to Beginning of Relief of Symptoms
The time to beginning of relief of symptoms at the location that showed the first visual analogue scale (VAS) score decrease of at least 20 mm from baseline score with persistence to the next timepoint, assessment timepoints were taken on pre-scheduled time-points after study drug administration: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours and 48 hours. Time to beginning of relief has been calculated as median time, by using the exact timepoints 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 | 68 minutes |
| 50 IU/kg rhC1INH | Time to Beginning of Relief of Symptoms | 122 minutes |
| Placebo | Time to Beginning of Relief of Symptoms | 258 minutes |
| 50 IU/kg Open-label rhC1INH | Time to Beginning of Relief of Symptoms | 62.5 minutes |
p-value: 0.001Log Rank
p-value: <0.001Log 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 timepoints were: baseline, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours and 48 hours. Time to minimal symtoms has been calculated by using the exact timepoints 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 Minimal Symptoms | 245 minutes |
| 50 IU/kg rhC1INH | Time to Minimal Symptoms | 246.5 minutes |
| Placebo | Time to Minimal Symptoms | 1101 minutes |
| 50 IU/kg Open-label rhC1INH | Time to Minimal Symptoms | 145 minutes |
p-value: 0.04Log Rank
p-value: <0.001Log Rank