Trial Outcomes & Findings for A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema (NCT NCT02316353)

Last Updated: 2018-11-14

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

126 participants

Primary outcome timeframe

Up to 146 weeks.

Results posted on

2018-11-14

Participant Flow

Participant milestones

Participant milestones
Measure	CSL830 (40) A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Overall Study STARTED	63	63
Overall Study COMPLETED	55	55
Overall Study NOT COMPLETED	8	8

Reasons for withdrawal

Reasons for withdrawal
Measure	CSL830 (40) A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Overall Study Pregnancy	1	3
Overall Study Adverse Event	1	3
Overall Study Withdrawal by Subject	6	2

Baseline Characteristics

A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CSL830 (40) n=63 Participants A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=63 Participants A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week	Total n=126 Participants Total of all reporting groups
Age, Categorical <=18 years	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	55 Participants n=5 Participants	50 Participants n=7 Participants	105 Participants n=5 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	8 Participants n=7 Participants	10 Participants n=5 Participants
Age, Continuous	40.8 years STANDARD_DEVIATION 14.96 • n=5 Participants	40.3 years STANDARD_DEVIATION 16.26 • n=7 Participants	40.5 years STANDARD_DEVIATION 15.56 • n=5 Participants
Sex: Female, Male Female	40 Participants n=5 Participants	36 Participants n=7 Participants	76 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	27 Participants n=7 Participants	50 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	59 Participants n=5 Participants	59 Participants n=7 Participants	118 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Canada	8 participants n=5 Participants	4 participants n=7 Participants	12 participants n=5 Participants
Region of Enrollment Romania	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment Hungary	1 participants n=5 Participants	5 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment United States	25 participants n=5 Participants	29 participants n=7 Participants	54 participants n=5 Participants
Region of Enrollment Czechia	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Italy	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment United Kingdom	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment Israel	6 participants n=5 Participants	8 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment Australia	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment Germany	13 participants n=5 Participants	9 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment Spain	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	CSL830 (40) n=63 Participants A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=70 Participants A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Person-time Incidence Rates (Subject Based) AEs Leading to Premature Study Discontinuation	0.01 participants with events/year	0.03 participants with events/year
Person-time Incidence Rates (Subject Based) Thromboembolic Events	0.00 participants with events/year	0.01 participants with events/year
Person-time Incidence Rates (Subject Based) Anaphylaxis	0.00 participants with events/year	0.00 participants with events/year
Person-time Incidence Rates (Subject Based) HAE Attacks Resulting in In-Patient Hospitalizatio	0.00 participants with events/year	0.00 participants with events/year
Person-time Incidence Rates (Subject Based) Solicited AEs Graded as Severe	0.00 participants with events/year	0.00 participants with events/year
Person-time Incidence Rates (Subject Based) Related SAEs Other Than Specified Above	0.00 participants with events/year	0.00 participants with events/year
Person-time Incidence Rates (Subject Based) Antibodies to C1-INH (Inhibitory + Non-inhibitory)	0.06 participants with events/year	0.06 participants with events/year

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	CSL830 (40) n=63 Participants A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=70 Participants A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
The Person-time Incidence Rates (Event Based) AEs Leading to Premature Study Discontinuation	0.01 events/year	0.03 events/year
The Person-time Incidence Rates (Event Based) Thromboembolic Events	0.00 events/year	0.01 events/year
The Person-time Incidence Rates (Event Based) Anaphylaxis	0.00 events/year	0.00 events/year
The Person-time Incidence Rates (Event Based) HAE Attacks Resulting in In-Patient Hospitalizatio	0.00 events/year	0.00 events/year
The Person-time Incidence Rates (Event Based) Solicited AEs Graded as Severe	0.00 events/year	0.00 events/year
The Person-time Incidence Rates (Event Based) Related SAEs Other Than Specified Above	0.00 events/year	0.00 events/year
The Person-time Incidence Rates (Event Based) Antibodies to C1-INH (Inhibitory + Non-inhibitory)	0.06 events/year	0.09 events/year

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	CSL830 (40) n=63 Participants A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=70 Participants A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Percentage of Subjects Who Have Solicited Adverse Events (AEs)	55.6 Percent of subjects	45.7 Percent of subjects

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	CSL830 (40) n=63 Participants A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=70 Participants A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Percentage of Injections Followed by At Least One Solicited Adverse Event	6.3 Percent of injections	5.1 Percent of injections

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	CSL830 (40) n=63 Participants A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=70 Participants A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Percentage of Subjects Who Become Seropositive for Human Immunodeficiency Virus (HIV-1/-2), Hepatitis B Virus, or Hepatitis C Virus.	0 Percent of Subjects	0 Percent of Subjects

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	CSL830 (40) n=63 Participants A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=63 Participants A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Percentage of Subjects Who Experience a Time-normalized HAE Attack Frequency of <1 HAE Attack Per 4-Week Period	79.4 Percent of Subjects	85.7 Percent of Subjects

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	CSL830 (40) n=62 Participants A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=60 Participants A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Percentage of Subjects Who Are Responders	93.5 Percent of Subjects Interval 84.6 to 97.5	91.7 Percent of Subjects Interval 81.9 to 96.4

Adverse Events

CSL830 (40)

Serious events: 4 serious events

Other events: 33 other events

Deaths: 0 deaths

CSL830 (60)

Serious events: 5 serious events

Other events: 28 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	CSL830 (40) n=63 participants at risk A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=70 participants at risk A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Injury, poisoning and procedural complications Contusion	1.6% 1/63 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	0.00% 0/70 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	1.6% 1/63 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	0.00% 0/70 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Nervous system disorders Dizziness	0.00% 0/63 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	1.4% 1/70 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Eye disorders Diplopia	0.00% 0/63 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	1.4% 1/70 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
General disorders Chest pain	0.00% 0/63 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	1.4% 1/70 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Hepatobiliary disorders Cholelithiasis	0.00% 0/63 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	1.4% 1/70 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Metabolism and nutrition disorders Dehydration	1.6% 1/63 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	0.00% 0/70 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Metabolism and nutrition disorders Hypokalemia	1.6% 1/63 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	0.00% 0/70 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Infections and infestations Pneumonia	0.00% 0/63 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	1.4% 1/70 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Infections and infestations Bronchitis	1.6% 1/63 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	0.00% 0/70 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.

Other adverse events

Additional Information

Michelle Hellstern

CSL Behring

Phone: 6102907515

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	CSL830 (40) n=63 participants at risk A low-volume dose of C1-INH (40 IU/kg) administered subcutaneously twice a week	CSL830 (60) n=70 participants at risk A high-volume dose of C1-INH (60 IU/kg) administered subcutaneously twice a week
Injury, poisoning and procedural complications Contusion	7.9% 5/63 • Number of events 5 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	1.4% 1/70 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Nervous system disorders Headache	15.9% 10/63 • Number of events 22 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	14.3% 10/70 • Number of events 19 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Nervous system disorders Migraine	6.3% 4/63 • Number of events 8 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	0.00% 0/70 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
General disorders Injection site pain	27.0% 17/63 • Number of events 211 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	14.3% 10/70 • Number of events 51 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
General disorders Injection site erythema	15.9% 10/63 • Number of events 45 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	17.1% 12/70 • Number of events 331 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
General disorders Injection site bruising	14.3% 9/63 • Number of events 56 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	10.0% 7/70 • Number of events 22 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
General disorders Injection site reaction	7.9% 5/63 • Number of events 75 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	11.4% 8/70 • Number of events 72 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
General disorders Injection site haematoma	9.5% 6/63 • Number of events 11 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	5.7% 4/70 • Number of events 12 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
General disorders Injection site induration	6.3% 4/63 • Number of events 19 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	4.3% 3/70 • Number of events 4 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
General disorders Injection site swelling	6.3% 4/63 • Number of events 19 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	2.9% 2/70 • Number of events 2 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Gastrointestinal disorders Nausea	7.9% 5/63 • Number of events 10 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	5.7% 4/70 • Number of events 14 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Gastrointestinal disorders Diarrhoea	6.3% 4/63 • Number of events 12 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	2.9% 2/70 • Number of events 2 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Gastrointestinal disorders Toothache	1.6% 1/63 • Number of events 1 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	5.7% 4/70 • Number of events 4 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Musculoskeletal and connective tissue disorders Arthralgia	9.5% 6/63 • Number of events 6 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	7.1% 5/70 • Number of events 5 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Musculoskeletal and connective tissue disorders Back pain	11.1% 7/63 • Number of events 7 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	4.3% 3/70 • Number of events 4 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Musculoskeletal and connective tissue disorders Myalgia	6.3% 4/63 • Number of events 6 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	1.4% 1/70 • Number of events 6 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Infections and infestations Nasopharyngitis	19.0% 12/63 • Number of events 23 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	30.0% 21/70 • Number of events 36 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Infections and infestations Upper respiratory tract infection	12.7% 8/63 • Number of events 10 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	11.4% 8/70 • Number of events 10 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Infections and infestations Urinary tract infection	4.8% 3/63 • Number of events 4 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	8.6% 6/70 • Number of events 6 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Infections and infestations Bronchitis	11.1% 7/63 • Number of events 7 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	2.9% 2/70 • Number of events 2 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.
Infections and infestations Sinusitis	6.3% 4/63 • Number of events 4 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.	5.7% 4/70 • Number of events 7 • 146 weeks per subject n=70 because 7 subjects titrated up from the 40 IU/kg arm and will be displayed in both arms.