Hereditary Angioedema Types I and II
Conditions
Keywords
Hereditary Angioedema
Brief summary
The aim of this study is to assess the efficacy of C1-esterase inhibitor in preventing hereditary angioedema attacks when it is administered under the skin of subjects with hereditary angioedema. The safety of C1-esterase inhibitor will also be assessed. Each subject will enter a run-in period of up to 8-weeks. Subjects who complete the run-in period and who are eligible will then enter the treatment phase which comprises two sequential treatment periods. In the treatment phase, subjects will be randomized to one of four arms consisting of treatment with low- or higher-volume C1-esterase inhibitor in one treatment period and treatment with low- or higher-volume placebo in the other treatment period. The study will measure the number of hereditary angioedema attacks that subjects experience while receiving each treatment.
Interventions
BIOLOGICALLow-volume C1-esterase inhibitor
BIOLOGICALHigher-volume C1-esterase inhibitor
BIOLOGICALLow-volume placebo
BIOLOGICALHigher-volume placebo
Sponsors
CSL Behring
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Run-In Period Inclusion Criteria: * Males or females aged 12 years or older. * A clinical diagnosis of hereditary angioedema type I or II. * Hereditary angioedema attacks over a consecutive 2-month period that required acute treatment, medical attention, or caused significant functional impairment. * For subjects who have used oral therapy for prophylaxis against HAE attacks within 3 months of Screening: use of a stable regimen within 3 months of Screening, with no plans to change. Eligibility Criteria for Entering Treatment Period 1: * Laboratory confirmation of type I or type II hereditary angioedema, including C1-esterase inhibitor functional activity less than 50% AND C4 antigen level below the laboratory reference range. * No clinically significant abnormalities as assessed using laboratory parameters. * During participation in the run-in period, subjects must have experienced hereditary angioedema attacks that required acute treatment, required medical attention, or caused significant functional impairment.
Exclusion criteria
Run-In Period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Time-normalized Number of Hereditary Angioedema Attacks | During the treatment phase, up to 28 weeks. | The time normalized number of HAE attacks as reported by the investigator per subject was calculated as: The total number of HAE attacks per subject and per treatment period / length of stay of subject in treatment period (days), Where length of stay of subject in treatment period was calculated as: Date of last day of subject in treatment period - date of first day of Week 3 of subject in treatment period + 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-Normalized Number of Uses of Rescue Medication | During the treatment phase, up to 28 weeks. | The time-normalized number of uses of rescue medication during treatment with C1-esterase inhibitor or placebo |
| Percentage of Subjects With Adverse Events (AEs) Within 24 Hours of C1-esterase Inhibitor or Placebo Administration | Within 24 hours of C1-esterase inhibitor or placebo administration. | — |
| Percentage of Subjects With a ≥ 50% Reduction in the Number of Hereditary Angioedema Attacks by CSL830 Treatment | During the treatment phase, up to 28 weeks. | The percentage reduction (%) in the time normalized number of HAE attacks was calculated as: 100 x \[1 - (the time normalized number of HAE attacks when treated with CSL830) / (the time normalized number of HAE attacks when treated with placebo)\]. A subject is classed as a responder if the percentage reduction is \>= 50%. |
| Percentage of Subjects Experiencing Solicited AEs (Injection Site Reactions) | During the treatment phase, up to 32 weeks. | The percentage of subjects experiencing solicited local AEs (discomfort \[eg, pain, burning\], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo. |
| Injections Resulting in Solicited AEs (Injection Site Reactions) | During the treatment phase, up to 32 weeks. | The rate/injection of injections of C1-esterase inhibitor or placebo that were followed by solicited local AEs (discomfort \[eg, pain, burning\], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo. Rate/Injection = Number of events/number of injections. |
| Percentage of Subjects With AEs or Other Specified Safety Events. | During the treatment phase, up to 32 weeks. | The percentage of subjects experiencing the following during treatment with CSL830 and placebo: unsolicited AEs, serious AEs, suspected adverse drug reactions, increased risk scores for deep vein thrombosis and pulmonary embolism, thromboembolic events, inhibitory anti C1 INH antibodies, or clinically significant abnormalities in laboratory assessments. |
Countries
Australia, Canada, Czechia, Hungary, Israel, Italy, Romania, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CSL830 (40)/Placebo High | 45 |
| CSL830 (60)/Placebo Low | 45 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 | Adverse Event | 1 | 0 | 0 | 1 |
| Period 1 | non-compliance | 1 | 0 | 0 | 1 |
| Period 1 | Physician Decision | 0 | 0 | 1 | 0 |
| Period 1 | Withdrawal by Subject | 0 | 1 | 1 | 1 |
| Period 2 | Adverse Event | 0 | 0 | 0 | 1 |
| Period 2 | Lack of Efficacy | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | CSL830 (40)/Placebo High | CSL830 (60)/Placebo Low | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 4 Participants | 7 Participants |
| Age, Categorical >=65 years | 4 Participants | 3 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 38 Participants | 38 Participants | 76 Participants |
| Age, Continuous | 42.4 years STANDARD_DEVIATION 14.41 | 36.8 years STANDARD_DEVIATION 14.921 | 39.6 years STANDARD_DEVIATION 14.85 |
| Region of Enrollment Australia | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Canada | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Czechia | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Hungary | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Israel | 3 participants | 6 participants | 9 participants |
| Region of Enrollment Italy | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Romania | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Spain | 3 participants | 1 participants | 4 participants |
| Region of Enrollment United Kingdom | 2 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 28 participants | 26 participants | 54 participants |
| Sex: Female, Male Female | 28 Participants | 32 Participants | 60 Participants |
| Sex: Female, Male Male | 17 Participants | 13 Participants | 30 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 | 0 / 43 | 0 / 43 | 0 / 44 | 0 / 42 |
| other Total, other adverse events | 10 / 43 | 17 / 43 | 12 / 44 | 12 / 42 |
| serious Total, serious adverse events | 1 / 43 | 0 / 43 | 1 / 44 | 1 / 42 |
Outcome results
Primary
The Time-normalized Number of Hereditary Angioedema Attacks
The time normalized number of HAE attacks as reported by the investigator per subject was calculated as: The total number of HAE attacks per subject and per treatment period / length of stay of subject in treatment period (days), Where length of stay of subject in treatment period was calculated as: Date of last day of subject in treatment period - date of first day of Week 3 of subject in treatment period + 1.
Time frame: During the treatment phase, up to 28 weeks.
Population: Intention-to-treat (ITT) population consisted of all subjects who provided informed consent / assent and were randomized, regardless of whether they received investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CSL830 (40) | The Time-normalized Number of Hereditary Angioedema Attacks | 0.04 attacks/day | Standard Error 0.011 |
| CSL830 (60) | The Time-normalized Number of Hereditary Angioedema Attacks | 0.02 attacks/day | Standard Error 0.009 |
| Placebo High | The Time-normalized Number of Hereditary Angioedema Attacks | 0.12 attacks/day | Standard Error 0.011 |
| Placebo Low | The Time-normalized Number of Hereditary Angioedema Attacks | 0.13 attacks/day | Standard Error 0.009 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
p-value: =0.114Mixed Models Analysis
Secondary
Injections Resulting in Solicited AEs (Injection Site Reactions)
The rate/injection of injections of C1-esterase inhibitor or placebo that were followed by solicited local AEs (discomfort \[eg, pain, burning\], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo. Rate/Injection = Number of events/number of injections.
Time frame: During the treatment phase, up to 32 weeks.
Population: SP
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Injections Resulting in Solicited AEs (Injection Site Reactions) | 0.21 injection site reactions/injection |
| CSL830 (60) | Injections Resulting in Solicited AEs (Injection Site Reactions) | 0.08 injection site reactions/injection |
| Placebo High | Injections Resulting in Solicited AEs (Injection Site Reactions) | 0.12 injection site reactions/injection |
| Placebo Low | Injections Resulting in Solicited AEs (Injection Site Reactions) | 0.05 injection site reactions/injection |
Secondary
Percentage of Subjects Experiencing Solicited AEs (Injection Site Reactions)
The percentage of subjects experiencing solicited local AEs (discomfort \[eg, pain, burning\], swelling, bruising, or itching at the investigational product injection site) during treatment with CSL830 and placebo.
Time frame: During the treatment phase, up to 32 weeks.
Population: SP
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Percentage of Subjects Experiencing Solicited AEs (Injection Site Reactions) | 27.9 percentage of participants |
| CSL830 (60) | Percentage of Subjects Experiencing Solicited AEs (Injection Site Reactions) | 34.9 percentage of participants |
| Placebo High | Percentage of Subjects Experiencing Solicited AEs (Injection Site Reactions) | 22.7 percentage of participants |
| Placebo Low | Percentage of Subjects Experiencing Solicited AEs (Injection Site Reactions) | 26.2 percentage of participants |
Secondary
Percentage of Subjects With a ≥ 50% Reduction in the Number of Hereditary Angioedema Attacks by CSL830 Treatment
The percentage reduction (%) in the time normalized number of HAE attacks was calculated as: 100 x \[1 - (the time normalized number of HAE attacks when treated with CSL830) / (the time normalized number of HAE attacks when treated with placebo)\]. A subject is classed as a responder if the percentage reduction is \>= 50%.
Time frame: During the treatment phase, up to 28 weeks.
Population: ITT. Subjects whose time-normalized number of attacks could not be calculated in one or both CSL830 treatment periods were excluded from the analysis. Percentages are based on the number of subjects included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Percentage of Subjects With a ≥ 50% Reduction in the Number of Hereditary Angioedema Attacks by CSL830 Treatment | 76.2 percentage of participants |
| CSL830 (60) | Percentage of Subjects With a ≥ 50% Reduction in the Number of Hereditary Angioedema Attacks by CSL830 Treatment | 90.0 percentage of participants |
95% CI: [-2.8, 29.7]
Secondary
Percentage of Subjects With Adverse Events (AEs) Within 24 Hours of C1-esterase Inhibitor or Placebo Administration
Time frame: Within 24 hours of C1-esterase inhibitor or placebo administration.
Population: The Safety Population (SP) consisted of all subjects who provided informed consent / assent, were randomized, and received at least 1 dose (or partial dose) of investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Percentage of Subjects With Adverse Events (AEs) Within 24 Hours of C1-esterase Inhibitor or Placebo Administration | 58.1 percentage of participants |
| CSL830 (60) | Percentage of Subjects With Adverse Events (AEs) Within 24 Hours of C1-esterase Inhibitor or Placebo Administration | 60.5 percentage of participants |
| Placebo High | Percentage of Subjects With Adverse Events (AEs) Within 24 Hours of C1-esterase Inhibitor or Placebo Administration | 45.5 percentage of participants |
| Placebo Low | Percentage of Subjects With Adverse Events (AEs) Within 24 Hours of C1-esterase Inhibitor or Placebo Administration | 54.8 percentage of participants |
Secondary
Percentage of Subjects With AEs or Other Specified Safety Events.
The percentage of subjects experiencing the following during treatment with CSL830 and placebo: unsolicited AEs, serious AEs, suspected adverse drug reactions, increased risk scores for deep vein thrombosis and pulmonary embolism, thromboembolic events, inhibitory anti C1 INH antibodies, or clinically significant abnormalities in laboratory assessments.
Time frame: During the treatment phase, up to 32 weeks.
Population: SP
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Percentage of Subjects With AEs or Other Specified Safety Events. | 67.4 percentage of participants |
| CSL830 (60) | Percentage of Subjects With AEs or Other Specified Safety Events. | 69.8 percentage of participants |
| Placebo High | Percentage of Subjects With AEs or Other Specified Safety Events. | 61.4 percentage of participants |
| Placebo Low | Percentage of Subjects With AEs or Other Specified Safety Events. | 71.4 percentage of participants |
Secondary
Time-Normalized Number of Uses of Rescue Medication
The time-normalized number of uses of rescue medication during treatment with C1-esterase inhibitor or placebo
Time frame: During the treatment phase, up to 28 weeks.
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CSL830 (40) | Time-Normalized Number of Uses of Rescue Medication | 0.04 rescue medication uses/day | Standard Error 0.042 |
| CSL830 (60) | Time-Normalized Number of Uses of Rescue Medication | 0.01 rescue medication uses/day | Standard Error 0.011 |
| Placebo High | Time-Normalized Number of Uses of Rescue Medication | 0.18 rescue medication uses/day | Standard Error 0.04 |
| Placebo Low | Time-Normalized Number of Uses of Rescue Medication | 0.13 rescue medication uses/day | Standard Error 0.011 |
p-value: <0.001Mixed Models Analysis
p-value: =0.018Mixed Models Analysis
p-value: =0.31Mixed Models Analysis