Hereditary Angioedema
Conditions
Keywords
Hereditary Angioedema, HAE, Angioedema, Recombinant C1 Inhibitor, rhC1INH
Brief summary
This study is being conducted to confirm the efficacy, safety, and immunogenicity of recombinant human C1 inhibitor (rhC1INH) at a dose of 50 U/kg when used for the treatment of acute angioedema attacks in Hereditary Angioedema (HAE) patients.
Detailed description
HAE is characterized by recurrent localized angioedema caused by uncontrolled activation of the complement and contact systems due to a congenital deficiency of functional C1 inhibitor. rhC1INH has been developed to offer a more widely available therapeutic alternative to the existing plasma-derived C1INH (pdC1INH) products that have been used in the treatment of acute angioedema attacks patients with HAE. Patients who have qualified for enrollment in advance and who present to a study center within 5 hours of onset of an attack will be evaluated for eligibility. 75 eligible patients will be randomized (3:2) to receive an intravenous infusion of rhC1INH or saline in a double-blind fashion. Open-label rhC1INH may be provided as rescue medication to patients who do not experience the beginning of relief within 4 hours or who experience life-threatening oropharyngeal-laryngeal angioedema symptoms. Any patient having received a randomized treatment will be allowed to receive treatment with rhC1INH in an open-label fashion for subsequent eligible attacks.
Interventions
DRUGrhC1INH
One i.v. injection of rhC1INH at the dose of 50 U/kg, for patients up to 84 kg; one i.v. injection of rhC1INH at the dose of 4200U (2 vials) for patients of 84 kg body weight or greater.
DRUGPlacebo (Saline)
One i.v. injection of saline (NaCl 0.9% w/v), equivalent in volume to the active treatment
Sponsors
Pharming Technologies B.V.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged at least 13 years * Signed written informed consent * Clear clinical and laboratory diagnosis of HAE with baseline plasma level of functional C1INH of less than 50% of normal * Willingness and ability to comply with all protocol procedures * Clinical symptoms of an eligible HAE attack with onset less than 5 hours before the time of initial evaluation
Exclusion criteria
* Medical history of allergy to rabbits or rabbit-derived products (including rhC1INH), or positive anti-rabbit dander IgE test (cut off \>0.35 kU/L; ImmunoCap® assay; Phadia or equivalent). * A diagnosis of acquired C1INH deficiency (AAE) * Pregnancy, or breastfeeding, or current intention to become pregnant * Treatment with any investigational drug in the past 30 days * Known or suspected addiction to drug and/or alcohol abuse * Suspicion for an alternate explanation of the symptoms other than acute HAE attack
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Beginning of Relief of Symptoms | Patients observed for 24 hours | Time to beginning of relief is the time lapsed from the beginning of the infusion of study medication to the beginning of a beneficial effect based on patient's responses to the Treatmetn Effect Questionnaire (TEQ) for the primary attack location. The beginning of relief is defined as the first timepoint at which * The patient reports any of the following answers for TEQ question 1: A little better, Better or Much better; and; * The patient reports the following answer for TEQ question 2: Yes; and, * There is persistence in improvement at the next assessment time, i.e.either the same or a better response to Question 1 and Yes to Question 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Minimal Symptoms | 24 hours | The key secondary efficacy endpoint was the time to minimal symptoms at all locations. The time to achieving minimal symptoms was defined as an answer of Yes to TEQ question 3. |
Countries
Bulgaria, Canada, Hungary, Israel, Italy, North Macedonia, Poland, Romania, Serbia, South Africa, United States
Participant flow
Recruitment details
During the double blind phase of the study, patients were randomized once to receive rhC1INH or Saline in a ratio of 3:2. After the randomized treatment, patiënts with subsequent attacks could be trated with open-label rhC1INH.
Pre-assignment details
Patients could be enrolled into the open-label phase of the study after the initial randomized treatment.
Participants by arm
| Arm | Count |
|---|---|
| rhC1INH rhC1INH: One i.v. injection of rhC1INH at the dose of 50 U/kg, for patients up to 84 kg; one i.v. injection of rhC1INH at the dose of 4200U (2 vials) for patients of 84 kg body weight or greater. | 44 |
| Placebo (Saline) Placebo (Saline): One i.v. injection of saline (NaCl 0.9% w/v), equivalent in volume to the active treatment | 31 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Phase | randomized not treated | 1 | 0 |
Baseline characteristics
| Characteristic | rhC1INH | Placebo (Saline) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 29 Participants | 71 Participants |
| Sex: Female, Male Female | 28 Participants | 19 Participants | 47 Participants |
| Sex: Female, Male Male | 16 Participants | 12 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 56 | 4 / 18 |
| serious Total, serious adverse events | 1 / 56 | 0 / 18 |
Outcome results
Primary
Time to Beginning of Relief of Symptoms
Time to beginning of relief is the time lapsed from the beginning of the infusion of study medication to the beginning of a beneficial effect based on patient's responses to the Treatmetn Effect Questionnaire (TEQ) for the primary attack location. The beginning of relief is defined as the first timepoint at which * The patient reports any of the following answers for TEQ question 1: A little better, Better or Much better; and; * The patient reports the following answer for TEQ question 2: Yes; and, * There is persistence in improvement at the next assessment time, i.e.either the same or a better response to Question 1 and Yes to Question 2.
Time frame: Patients observed for 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rhC1INH | Time to Beginning of Relief of Symptoms | 90 minutes |
| Placebo (Saline) | Time to Beginning of Relief of Symptoms | 152 minutes |
Secondary
Time to Minimal Symptoms
The key secondary efficacy endpoint was the time to minimal symptoms at all locations. The time to achieving minimal symptoms was defined as an answer of Yes to TEQ question 3.
Time frame: 24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rhC1INH | Time to Minimal Symptoms | 303 minutes |
| Placebo (Saline) | Time to Minimal Symptoms | 483 minutes |