Hereditary Angioedema Types I and II
Conditions
Brief summary
The aim of this study is to assess the long-term safety of C1-esterase inhibitor (C1-INH) in preventing hereditary angioedema (HAE) attacks when it is administered under the skin of subjects with HAE. The safety of participating subjects will be assessed for up to 54 weeks. The long-term efficacy of C1-INH will also be assessed. Each eligible subject will enter the treatment phase, wherein subjects will be randomized to treatment with either low- or medium-volume C1-INH. Subjects who have an insufficient treatment response during the study will be given an opportunity to undergo a dose increase. The study aims to enroll eligible subjects who completed study CSL830\_3001 (NCT01912456). Subjects who did not participate in study CSL830\_3001 may also participate, if eligible and if space permits. Subjects from the United States (US) who complete Treatment Period 2 will be allowed to participate in an Extension Period. During the Extension Period participating US subjects will continue to receive treatment with open-label CSL830 for up to an additional 88 weeks.
Interventions
BIOLOGICALC1-esterase inhibitor
Sponsors
CSL Behring
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females aged 6 years or older. * A confirmed diagnosis of HAE type I or II. * HAE 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 first study visit: use of a stable regimen within 3 months of the first study visit.
Exclusion criteria
* Incurable malignancies. * Any clinical condition that will interfere with the evaluation of C1-INH therapy. * Clinically significant history of poor response to C1-esterase therapy for the management of HAE. * Suspected or confirmed diagnosis of acquired HAE or HAE with normal C1-INH. * Inability to have HAE managed pharmacologically with on-demand treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Person-time Incidence Rates (Subject Based) | Up to 146 weeks. | Subject-based Analysis for Person-Time Incidence Rate = (the total number of subjects who experienced the event during the respective treatment) / (the sum of the date each subject experienced the event - the subject's start date + 1 day) / (365.25 days). The analysis population for this endpoint was the Safety Population: the Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830. |
| The Person-time Incidence Rates (Event Based) | Up to 146 weeks. | Event-based Analysis for Person-Time Incidence Rate = (the total number of events documented during the respective treatment) / (the sum of each subject's end date - the subject's start date + 1 day) / (365.25 days). The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Who Become Seropositive for Human Immunodeficiency Virus (HIV-1/-2), Hepatitis B Virus, or Hepatitis C Virus. | Up to 146 weeks | Blood samples to be tested for HIV-1/-2, HBV, and HCV. The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830. |
| Percentage of Subjects Who Have Solicited Adverse Events (AEs) | Up to 146 weeks | The number of subjects having at least 1 solicited local AE during a treatment were divided by the number of subjects in the corresponding treatment. The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830. |
| Percentage of Subjects Who Are Responders | Up to 146 weeks | A responder was defined as a subject with a ≥ 50% reduction in the time-normalized number of HAE attacks on CSL830 relative to the time-normalized number of HAE attacks used to qualify for participation in the current study. The analysis population for this endpoint was the Intent-to-Treat (ITT) Population: The ITT Population comprised all subjects who provided informed consent / assent and were randomized, regardless of whether or not they received CSL830. Not all subjects in the ITT were available for this outcome measure. |
| Percentage of Subjects Who Experience a Time-normalized HAE Attack Frequency of <1 HAE Attack Per 4-Week Period | Up to 146 weeks | The percentage of subjects with a time-normalized merged HAE attack frequency of \<1 HAE attack per 4-week period. The analysis population for this endpoint was the Intent-to-Treat (ITT) Population: The ITT Population comprised all subjects who provided informed consent / assent and were randomized, regardless of whether or not they received CSL 830. |
| Percentage of Injections Followed by At Least One Solicited Adverse Event | Up to 146 weeks | The percent of injections followed by at least one solicited adverse event. The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830. This was assessed across all participants, calculated as total number of events following injections / total number of injections across all participants, in each Arm. |
Countries
Australia, Canada, Czechia, Germany, Hungary, Israel, Italy, Romania, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CSL830 (40) A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week | 63 |
| CSL830 (60) A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week | 63 |
| Total | 126 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Pregnancy | 1 | 3 |
| Overall Study | Withdrawal by Subject | 6 | 2 |
Baseline characteristics
| Characteristic | CSL830 (60) | Total | CSL830 (40) |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 11 Participants | 6 Participants |
| Age, Categorical >=65 years | 8 Participants | 10 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 50 Participants | 105 Participants | 55 Participants |
| Age, Continuous | 40.3 years STANDARD_DEVIATION 16.26 | 40.5 years STANDARD_DEVIATION 15.56 | 40.8 years STANDARD_DEVIATION 14.96 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 8 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants | 118 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Australia | 2 participants | 3 participants | 1 participants |
| Region of Enrollment Canada | 4 participants | 12 participants | 8 participants |
| Region of Enrollment Czechia | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Germany | 9 participants | 22 participants | 13 participants |
| Region of Enrollment Hungary | 5 participants | 6 participants | 1 participants |
| Region of Enrollment Israel | 8 participants | 14 participants | 6 participants |
| Region of Enrollment Italy | 1 participants | 4 participants | 3 participants |
| Region of Enrollment Romania | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Spain | 2 participants | 4 participants | 2 participants |
| Region of Enrollment United Kingdom | 1 participants | 2 participants | 1 participants |
| Region of Enrollment United States | 29 participants | 54 participants | 25 participants |
| Sex: Female, Male Female | 36 Participants | 76 Participants | 40 Participants |
| Sex: Female, Male Male | 27 Participants | 50 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 0 / 70 |
| other Total, other adverse events | 33 / 63 | 28 / 70 |
| serious Total, serious adverse events | 4 / 63 | 5 / 70 |
Outcome results
Primary
Person-time Incidence Rates (Subject Based)
Subject-based Analysis for Person-Time Incidence Rate = (the total number of subjects who experienced the event during the respective treatment) / (the sum of the date each subject experienced the event - the subject's start date + 1 day) / (365.25 days). The analysis population for this endpoint was the Safety Population: the Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.
Time frame: Up to 146 weeks.
Population: Safety population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CSL830 (40) | Person-time Incidence Rates (Subject Based) | Thromboembolic Events | 0.00 participants with events/year |
| CSL830 (40) | Person-time Incidence Rates (Subject Based) | HAE Attacks Resulting in In-Patient Hospitalizatio | 0.00 participants with events/year |
| CSL830 (40) | Person-time Incidence Rates (Subject Based) | Solicited AEs Graded as Severe | 0.00 participants with events/year |
| CSL830 (40) | Person-time Incidence Rates (Subject Based) | Related SAEs Other Than Specified Above | 0.00 participants with events/year |
| CSL830 (40) | Person-time Incidence Rates (Subject Based) | AEs Leading to Premature Study Discontinuation | 0.01 participants with events/year |
| CSL830 (40) | Person-time Incidence Rates (Subject Based) | Antibodies to C1-INH (Inhibitory + Non-inhibitory) | 0.06 participants with events/year |
| CSL830 (40) | Person-time Incidence Rates (Subject Based) | Anaphylaxis | 0.00 participants with events/year |
| CSL830 (60) | Person-time Incidence Rates (Subject Based) | Antibodies to C1-INH (Inhibitory + Non-inhibitory) | 0.06 participants with events/year |
| CSL830 (60) | Person-time Incidence Rates (Subject Based) | HAE Attacks Resulting in In-Patient Hospitalizatio | 0.00 participants with events/year |
| CSL830 (60) | Person-time Incidence Rates (Subject Based) | AEs Leading to Premature Study Discontinuation | 0.03 participants with events/year |
| CSL830 (60) | Person-time Incidence Rates (Subject Based) | Thromboembolic Events | 0.01 participants with events/year |
| CSL830 (60) | Person-time Incidence Rates (Subject Based) | Solicited AEs Graded as Severe | 0.00 participants with events/year |
| CSL830 (60) | Person-time Incidence Rates (Subject Based) | Related SAEs Other Than Specified Above | 0.00 participants with events/year |
| CSL830 (60) | Person-time Incidence Rates (Subject Based) | Anaphylaxis | 0.00 participants with events/year |
Primary
The Person-time Incidence Rates (Event Based)
Event-based Analysis for Person-Time Incidence Rate = (the total number of events documented during the respective treatment) / (the sum of each subject's end date - the subject's start date + 1 day) / (365.25 days). The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.
Time frame: Up to 146 weeks.
Population: Safety population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CSL830 (40) | The Person-time Incidence Rates (Event Based) | Thromboembolic Events | 0.00 events/year |
| CSL830 (40) | The Person-time Incidence Rates (Event Based) | Anaphylaxis | 0.00 events/year |
| CSL830 (40) | The Person-time Incidence Rates (Event Based) | Related SAEs Other Than Specified Above | 0.00 events/year |
| CSL830 (40) | The Person-time Incidence Rates (Event Based) | Antibodies to C1-INH (Inhibitory + Non-inhibitory) | 0.06 events/year |
| CSL830 (40) | The Person-time Incidence Rates (Event Based) | AEs Leading to Premature Study Discontinuation | 0.01 events/year |
| CSL830 (40) | The Person-time Incidence Rates (Event Based) | HAE Attacks Resulting in In-Patient Hospitalizatio | 0.00 events/year |
| CSL830 (40) | The Person-time Incidence Rates (Event Based) | Solicited AEs Graded as Severe | 0.00 events/year |
| CSL830 (60) | The Person-time Incidence Rates (Event Based) | Antibodies to C1-INH (Inhibitory + Non-inhibitory) | 0.09 events/year |
| CSL830 (60) | The Person-time Incidence Rates (Event Based) | HAE Attacks Resulting in In-Patient Hospitalizatio | 0.00 events/year |
| CSL830 (60) | The Person-time Incidence Rates (Event Based) | Anaphylaxis | 0.00 events/year |
| CSL830 (60) | The Person-time Incidence Rates (Event Based) | Solicited AEs Graded as Severe | 0.00 events/year |
| CSL830 (60) | The Person-time Incidence Rates (Event Based) | AEs Leading to Premature Study Discontinuation | 0.03 events/year |
| CSL830 (60) | The Person-time Incidence Rates (Event Based) | Related SAEs Other Than Specified Above | 0.00 events/year |
| CSL830 (60) | The Person-time Incidence Rates (Event Based) | Thromboembolic Events | 0.01 events/year |
Secondary
Percentage of Injections Followed by At Least One Solicited Adverse Event
The percent of injections followed by at least one solicited adverse event. The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830. This was assessed across all participants, calculated as total number of events following injections / total number of injections across all participants, in each Arm.
Time frame: Up to 146 weeks
Population: Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Percentage of Injections Followed by At Least One Solicited Adverse Event | 6.3 Percent of injections |
| CSL830 (60) | Percentage of Injections Followed by At Least One Solicited Adverse Event | 5.1 Percent of injections |
Secondary
Percentage of Subjects Who Are Responders
A responder was defined as a subject with a ≥ 50% reduction in the time-normalized number of HAE attacks on CSL830 relative to the time-normalized number of HAE attacks used to qualify for participation in the current study. The analysis population for this endpoint was the Intent-to-Treat (ITT) Population: The ITT Population comprised all subjects who provided informed consent / assent and were randomized, regardless of whether or not they received CSL830. Not all subjects in the ITT were available for this outcome measure.
Time frame: Up to 146 weeks
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all subjects who provided informed consent / assent and were randomized, regardless of whether or not they received CSL830.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Percentage of Subjects Who Are Responders | 93.5 Percent of Subjects |
| CSL830 (60) | Percentage of Subjects Who Are Responders | 91.7 Percent of Subjects |
Secondary
Percentage of Subjects Who Become Seropositive for Human Immunodeficiency Virus (HIV-1/-2), Hepatitis B Virus, or Hepatitis C Virus.
Blood samples to be tested for HIV-1/-2, HBV, and HCV. The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.
Time frame: Up to 146 weeks
Population: Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Percentage of Subjects Who Become Seropositive for Human Immunodeficiency Virus (HIV-1/-2), Hepatitis B Virus, or Hepatitis C Virus. | 0 Percent of Subjects |
| CSL830 (60) | Percentage of Subjects Who Become Seropositive for Human Immunodeficiency Virus (HIV-1/-2), Hepatitis B Virus, or Hepatitis C Virus. | 0 Percent of Subjects |
Secondary
Percentage of Subjects Who Experience a Time-normalized HAE Attack Frequency of <1 HAE Attack Per 4-Week Period
The percentage of subjects with a time-normalized merged HAE attack frequency of \<1 HAE attack per 4-week period. The analysis population for this endpoint was the Intent-to-Treat (ITT) Population: The ITT Population comprised all subjects who provided informed consent / assent and were randomized, regardless of whether or not they received CSL 830.
Time frame: Up to 146 weeks
Population: Intent-to-Treat (ITT) Population: The ITT Population comprised all subjects who provided informed consent / assent and were randomized, regardless of whether or not they received CSL 830.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Percentage of Subjects Who Experience a Time-normalized HAE Attack Frequency of <1 HAE Attack Per 4-Week Period | 79.4 Percent of Subjects |
| CSL830 (60) | Percentage of Subjects Who Experience a Time-normalized HAE Attack Frequency of <1 HAE Attack Per 4-Week Period | 85.7 Percent of Subjects |
Secondary
Percentage of Subjects Who Have Solicited Adverse Events (AEs)
The number of subjects having at least 1 solicited local AE during a treatment were divided by the number of subjects in the corresponding treatment. The analysis population for this endpoint was the Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.
Time frame: Up to 146 weeks
Population: Safety Population: The Safety Population comprised all subjects who provided informed consent / assent, who were randomized, and who received at least 1 dose or a partial dose of CSL830.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CSL830 (40) | Percentage of Subjects Who Have Solicited Adverse Events (AEs) | 55.6 Percent of subjects |
| CSL830 (60) | Percentage of Subjects Who Have Solicited Adverse Events (AEs) | 45.7 Percent of subjects |