Hereditary Angioedema
Conditions
Keywords
C1 Inhibitor, Hereditary angioedema, Acute HAE attack
Brief summary
HAE is a rare disorder characterized by functional C1 esterase inhibitor deficiency. If not treated adequately, the acute attacks of HAE can be life-threatening and may even result in fatalities, especially in case of swelling of the larynx. This clinical Phase 2/Phase 3 study was designed to provide clinically relevant data on dosing, efficacy and safety in subjects with HAE.
Detailed description
For each subject, only a single abdominal or facial attack was treated and evaluated. After receiving treatment, subjects were observed for a minimum of 4 hours, after which they could be discharged from the study center if they reported onset of symptom relief. Starting from 4 hours after treatment, subjects who reported insufficient or no symptom relief could receive a second dose of double-blind treatment (called rescue medication) as follows: C1-INH 20 U/kg bw for subjects initially receiving placebo, C1-INH 10 U/kg bw for subjects initially receiving C1-INH 10 U/kg bw, and placebo for subjects initially receiving C1-INH 20 U/kg bw. The study was defined to be successful if the primary outcome measure and at least one of the secondary outcome measures were met in the comparison between the C1-INH 20 U/kg bw group and the Placebo group.
Interventions
BIOLOGICALC1 Esterase Inhibitor
Single application of C1-INH administered intravenously by slow injection or infusion at a recommended rate of 4mL/min.
BIOLOGICALPlacebo
Single application of physiological saline solution equivalent to the volume calculated for subjects in the C1-INH 20 U/kg bw arm.
Sponsors
CSL Behring
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Documented congenital C1-INH deficiency * Acute facial or abdominal HAE attack Key
Exclusion criteria
* Acquired angioedema * Treatment with any other investigational drug within the last 30 days before study entry * Treatment with any C1-INH concentrate within the previous 7 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Start of Relief of Symptoms From HAE Attack | Up to 24 h after start of study treatment | The start of symptom relief was determined by subject self-assessment. Time to start of symptom relief was set to 24 hours if the subject received rescue medication (blinded study medication, narcotic analgesics, antiemetics, open-label C1-INH, or fresh frozen plasma) at any time point after the start of study treatment but before start of relief. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Worsened Intensity of Clinical HAE Symptoms | Baseline and between 2 and 4 h after start of study treatment | Includes any worsening of intensity of at least 1 of the HAE symptoms present at baseline. Routinely checked symptoms included pain, nausea, vomiting, cramps, and diarrhea. |
| Number of Vomiting Episodes | Within 4 h after start of study treatment | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Complete Resolution of All HAE Symptoms, Including Pain | Up to 24 h after start of study treatment | Complete resolution of symptoms was determined by subject self-assessment. |
| Number of Subjects Receiving Rescue Study Medication | Within 4 h after start of study treatment | — |
Countries
Argentina, Australia, Bulgaria, Canada, Czechia, Hungary, Israel, North Macedonia, Poland, Romania, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
This was a multinational study enrolling subjects at 36 study centers in 15 countries.
Pre-assignment details
A screening visit was performed before the subject presented with an hereditary angioedema (HAE) attack at the study center. Study entry was defined to occur with administration of study treatment. One subject enrolled received study treatment without being randomized and is listed separately in the participant flow.
Participants by arm
| Arm | Count |
|---|---|
| C1-INH 10 U/kg bw Baseline characteristics were calculated only for the intention to treat (ITT) and per protocol (PP) analysis populations, not for all enrolled subjects. Baseline data presented here are for subjects included in the ITT population. One (1) subject enrolled and randomized to the C1-INH 10 U/kg bw group was excluded from the ITT analysis population. | 39 |
| C1-INH 20 U/kg bw Baseline data presented here are for subjects included in the ITT population. All subjects enrolled and randomized to the C1-INH 20 U/kg bw arm were included in the ITT analysis population. | 43 |
| Placebo Baseline data presented here are for subjects included in the ITT population. All subjects enrolled and randomized to the Placebo arm were included in the ITT analysis population. | 42 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 3 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | C1-INH 10 U/kg bw | C1-INH 20 U/kg bw |
|---|---|---|---|---|
| Age, Continuous | 33.1 years STANDARD_DEVIATION 13.76 | 31.5 years STANDARD_DEVIATION 13.57 | 33.1 years STANDARD_DEVIATION 12.77 | 34.6 years STANDARD_DEVIATION 14.91 |
| Age, Customized 12 to < 17 years | 10 participants | 3 participants | 3 participants | 4 participants |
| Age, Customized 17 to < 65 years | 107 participants | 37 participants | 35 participants | 35 participants |
| Age, Customized 3 to < 12 years | 3 participants | 2 participants | 0 participants | 1 participants |
| Age, Customized >= 65 years | 4 participants | 0 participants | 1 participants | 3 participants |
| Intensity of Baseline HAE Attack Moderate | 85 Participants | 26 Participants | 32 Participants | 27 Participants |
| Intensity of Baseline HAE Attack Severe | 39 Participants | 16 Participants | 7 Participants | 16 Participants |
| Primary Disease Characteristic Missing | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Primary Disease Characteristic Type I HAE | 108 Participants | 38 Participants | 35 Participants | 35 Participants |
| Primary Disease Characteristic Type II HAE | 15 Participants | 4 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic | 5 Participants | 1 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 111 Participants | 37 Participants | 36 Participants | 38 Participants |
| Sex: Female, Male Female | 84 Participants | 28 Participants | 26 Participants | 30 Participants |
| Sex: Female, Male Male | 40 Participants | 14 Participants | 13 Participants | 13 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 | 10 / 39 | 10 / 46 | 18 / 41 |
| serious Total, serious adverse events | 0 / 39 | 0 / 46 | 0 / 41 |
Outcome results
Primary
Time to Start of Relief of Symptoms From HAE Attack
The start of symptom relief was determined by subject self-assessment. Time to start of symptom relief was set to 24 hours if the subject received rescue medication (blinded study medication, narcotic analgesics, antiemetics, open-label C1-INH, or fresh frozen plasma) at any time point after the start of study treatment but before start of relief.
Time frame: Up to 24 h after start of study treatment
Population: Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| C1-INH 10 U/kg bw | Time to Start of Relief of Symptoms From HAE Attack | 1.17 Hours | Full Range 10.513 |
| C1-INH 20 U/kg bw | Time to Start of Relief of Symptoms From HAE Attack | 0.5 Hours | Full Range 8.202 |
| Placebo | Time to Start of Relief of Symptoms From HAE Attack | 1.5 Hours | Full Range 11.481 |
p-value: 0.002595% CI: [-2.217, -0.033]Wilcoxon (Mann-Whitney)
Secondary
Number of Subjects With Worsened Intensity of Clinical HAE Symptoms
Includes any worsening of intensity of at least 1 of the HAE symptoms present at baseline. Routinely checked symptoms included pain, nausea, vomiting, cramps, and diarrhea.
Time frame: Baseline and between 2 and 4 h after start of study treatment
Population: Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-INH 10 U/kg bw | Number of Subjects With Worsened Intensity of Clinical HAE Symptoms | 8 Subjects |
| C1-INH 20 U/kg bw | Number of Subjects With Worsened Intensity of Clinical HAE Symptoms | 2 Subjects |
| Placebo | Number of Subjects With Worsened Intensity of Clinical HAE Symptoms | 13 Subjects |
Comparison: Worsened intensity was evaluated between 2 and 4 hours after start of study treatment relative to baseline for at least 1 of the HAE symptoms present at baseline.p-value: 0.001480% CI: [0.0392, 0.3023]Fisher Exact
Secondary
Number of Vomiting Episodes
Time frame: Within 4 h after start of study treatment
Population: Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| C1-INH 10 U/kg bw | Number of Vomiting Episodes | 0 Episodes per subject | Full Range 0.77 |
| C1-INH 20 U/kg bw | Number of Vomiting Episodes | 0 Episodes per subject | Full Range 0.41 |
| Placebo | Number of Vomiting Episodes | 0 Episodes per subject | Full Range 2.59 |
p-value: 0.0329Wilcoxon (Mann-Whitney)
Other Pre-specified
Number of Subjects Receiving Rescue Study Medication
Time frame: Within 4 h after start of study treatment
Population: Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-INH 10 U/kg bw | Number of Subjects Receiving Rescue Study Medication | 13 Subjects |
| C1-INH 20 U/kg bw | Number of Subjects Receiving Rescue Study Medication | 8 Subjects |
| Placebo | Number of Subjects Receiving Rescue Study Medication | 24 Subjects |
Comparison: This was an exploratory analysis.95% CI: [0.0642, 0.4575]
Other Pre-specified
Time to Complete Resolution of All HAE Symptoms, Including Pain
Complete resolution of symptoms was determined by subject self-assessment.
Time frame: Up to 24 h after start of study treatment
Population: Analysis was based on the ITT population which included all subjects receiving any portion of the randomized study medication.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| C1-INH 10 U/kg bw | Time to Complete Resolution of All HAE Symptoms, Including Pain | 20.00 Hours | Full Range 494.23 |
| C1-INH 20 U/kg bw | Time to Complete Resolution of All HAE Symptoms, Including Pain | 4.92 Hours | Full Range 314.347 |
| Placebo | Time to Complete Resolution of All HAE Symptoms, Including Pain | 7.79 Hours | Full Range 382.815 |
Comparison: This was an exploratory analysis.p-value: 0.023780% CI: [-5.15, -1.05]Wilcoxon (Mann-Whitney)