A Study to Evaluate the Clinical Pharmacology and Safety of C1-esterase Inhibitor Administered by the Subcutaneous Route

An Open-label, Cross-over, Dose-ranging Study to Evaluate the Pharmacokinetics, Pharmacodynamics and Safety of the Subcutaneous Administration of a Human Plasma-derived C1-esterase Inhibitor in Subjects With Hereditary Angioedema

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01576523

Enrollment

Registered

2012-04-12

Start date

2012-04-30

Completion date

2012-12-31

Last updated

2021-02-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hereditary Angioedema Types I and II

Brief summary

The aim of the study is to assess what happens to C1-esterase inhibitor that is administered under the skin of subjects with hereditary angioedema. Three different dosing regimens of C1-esterase inhibitor will be assessed. Each subject will be assigned to receive 2 of the 3 dosing regimens, each for 4 weeks. The activity and concentration of C1-esterase inhibitor in the blood will be measured during each 4-week period. The study will also examine how well C1-esterase inhibitor administered under the skin is tolerated by the subjects.

Interventions

BIOLOGICALC1-esterase inhibitor - single intravenous dose

A single intravenous dose of C1-esterase inhibitor (Berinert) at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor.

BIOLOGICALC1-esterase inhibitor - subcutaneous low dose

A low dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.

BIOLOGICALC1-esterase inhibitor - subcutaneous medium dose

A medium dose of C1-esterase inhibitor will be administered subcutaneously twice a week for four weeks.

BIOLOGICALC1-esterase inhibitor - subcutaneous high dose

A high dose of C1-esterase inhibitor will administered subcutaneously twice a week for four weeks.

Study design

Allocation

NON_RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

PREVENTION

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Males or females aged 18 years or older. * Laboratory-confirmed hereditary angioedema type I or II. * Less than two hereditary angioedema attacks per month in the last three months. * Body weight of 50.0 kg to 110.0 kg.

Exclusion criteria

* Receiving prophylactic C1-esterase inhibitor therapy. * Received C1-esterase inhibitor, ecallantide, icatibant or any blood products for the prevention or treatment of hereditary angioedema within 7 days before the screening visit. * Intends to use recombinant C1-esterase inhibitor or fresh frozen plasma for the acute treatment of hereditary angioedema during the study. * Received androgen therapy (e.g., danazol, oxandrolone, stanozolol, testosterone) within 30 days before the screening visit. * Female subjects who started taking or changed dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e., estrogen/progesterone-containing products) within 3 months prior to the screening visit. * Known or suspected hypersensitivity to the study product, or to any excipients of the study product. * Pregnancy or lactation.

Design outcomes

Primary

Measure	Time frame	Description
Modeled C1-esterase Inhibitor Functional Activity Trough Level	at the fourth week of each dosing regimen	Mean trough C1-esterase inhibitor functional activity of the low, medium and high subcutaneous dose regimens, based on modeling and simulation

Secondary

Measure	Time frame	Description
C1-esterase Inhibitor Concentration Trough Level	during the last week of 4-week dose regimen	Mean trough C1-esterase inhibitor concentration of the low, medium and high subcutaneous dose regimens
C4 Concentration Trough Level	during the last week of 4-week dose regimen	Mean trough C4 concentration of the low, medium and high subcutaneous dose regimens
As-observed C1-esterase Inhibitor Functional Activity Trough Level	during the last week of 4-week dose regimen	Mean trough C1-esterase inhibitor functional activity of the low, medium and high subcutaneous dose regimens
Change From Baseline in C1-esterase Inhibitor Concentration	Baseline and during the last week of 4-week dose regimen	Mean change from baseline of C1-esterase inhibitor concentration of the low, medium and high subcutaneous dose regimens
Change From Baseline in C4 Concentration	Baseline and during the last week of 4-week dose regimen	Mean change from baseline of C4 concentration of the low, medium and high subcutaneous dose regimens
Change From Baseline in C1-esterase Inhibitor Functional Activity	Baseline and during the last week of 4-week dose regimen	Mean change from baseline of C1-esterase inhibitor functional activity of the low, medium and high subcutaneous dose regimens

Countries

Germany, United States

Participant flow

Participants by arm

Arm	Count
Low, Then Medium, CSL830 Dose C1-esterase inhibitor - single intravenous dose(Berinert): A single intravenous dose of C1- esterase inhibitor at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor (CSL830). C1-esterase inhibitor - subcutaneous low dose (CSL830): A low dose of C1- esterase inhibitor (1500 IU) will be administered subcutaneously twice a week for four weeks, then C1-esterase inhibitor - subcutaneous medium dose (CSL830): A medium dose of C1-esterase inhibitor (3000 IU) will be administered subcutaneously twice a week for four weeks.	3
Medium, Then Low, CSL830 Dose C1-esterase inhibitor - single intravenous dose(Berinert): A single intravenous dose of C1- esterase inhibitor at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor (CSL830). C1-esterase inhibitor - subcutaneous medium dose (CSL830): A medium dose of C1-esterase inhibitor (3000 IU) will be administered subcutaneously twice a week for four weeks, then C1-esterase inhibitor - subcutaneous low dose (CSL830): A low dose of C1- esterase inhibitor (1500 IU) will be administered subcutaneously twice a week for four weeks.	3
Medium, Then High, CSL830 Dose C1-esterase inhibitor - single intravenous dose(Berinert): A single intravenous dose of C1- esterase inhibitor at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor (CSL830). C1-esterase inhibitor - subcutaneous medium dose (CSL830): A medium dose of C1-esterase inhibitor (3000 IU) will be administered subcutaneously twice a week for four weeks, then C1-esterase inhibitor - subcutaneous high dose (CSL830): A high dose of C1-esterase inhibitor (6000 IU) will administered subcutaneously twice a week for four weeks.	3
Low, Then High, CSL830 Dose C1-esterase inhibitor - single intravenous dose(Berinert): A single intravenous dose of C1- esterase inhibitor at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor (CSL830). C1-esterase inhibitor - subcutaneous low dose (CSL830): A low dose of C1- esterase inhibitor (1500 IU) will be administered subcutaneously twice a week for four weeks, then C1-esterase inhibitor - subcutaneous high dose (CSL830): A high dose of C1-esterase inhibitor (6000 IU) will administered subcutaneously twice a week for four weeks.	3
High, Then Low, CSL830 Dose C1-esterase inhibitor - single intravenous dose:(Berinert): A single intravenous dose of C1- esterase inhibitor at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor (CSL830). C1-esterase inhibitor - subcutaneous high dose (CSL830): A high dose of C1-esterase inhibitor (6000 IU) will be administered subcutaneously twice a week for four weeks, then C1-esterase inhibitor - subcutaneous low dose (CSL830): A low dose of C1- esterase inhibitor (1500 IU) will administered subcutaneously twice a week for four weeks.	3
High, Then Medium, CSL830 Dose C1-esterase inhibitor - single intravenous dose(Berinert): A single intravenous dose of C1- esterase inhibitor at 20 units per kg body weight will be administered to all subjects prior to receiving the first dose of subcutaneous C1-esterase inhibitor (CSL830). C1-esterase inhibitor - subcutaneous high dose (CSL830): A high dose of C1-esterase inhibitor (6000 IU) will be administered subcutaneously twice a week for four weeks, then C1-esterase inhibitor - subcutaneous medium dose (CSL830): A medium dose of C1-esterase inhibitor (3000 IU) will be administered subcutaneously twice a week for four weeks.	3
Total	18

Baseline characteristics

Characteristic	Low, Then Medium, CSL830 Dose	Medium, Then Low, CSL830 Dose	Medium, Then High, CSL830 Dose	Low, Then High, CSL830 Dose	High, Then Low, CSL830 Dose	High, Then Medium, CSL830 Dose	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Age, Categorical Between 18 and 65 years	3 Participants	3 Participants	2 Participants	3 Participants	3 Participants	3 Participants	17 Participants
Sex: Female, Male Female	2 Participants	2 Participants	1 Participants	2 Participants	2 Participants	2 Participants	11 Participants
Sex: Female, Male Male	1 Participants	1 Participants	2 Participants	1 Participants	1 Participants	1 Participants	7 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 / 18	0 / 12	0 / 12	0 / 12
other Total, other adverse events	4 / 18	10 / 12	8 / 12	9 / 12
serious Total, serious adverse events	1 / 18	0 / 12	0 / 12	1 / 12

Outcome results

Primary

Modeled C1-esterase Inhibitor Functional Activity Trough Level

Mean trough C1-esterase inhibitor functional activity of the low, medium and high subcutaneous dose regimens, based on modeling and simulation

Time frame: at the fourth week of each dosing regimen

Population: Complete Analysis Set (CAS) - Subjects received at least 1 dose (complete or incomplete) of the dosing regimen of CSL830 and provided at least 1 C1-INH functional activity measurement during the dosing regimen (prior to the use of any prohibited concomitant therapy or prohibited change in dosage of a concomitant therapy)

Arm	Measure	Value (MEAN)	Dispersion
CSL830 (Low Dose)	Modeled C1-esterase Inhibitor Functional Activity Trough Level	30.3 percent functional activity	Standard Deviation 9.07
CSL830 (Medium Dose)	Modeled C1-esterase Inhibitor Functional Activity Trough Level	45.9 percent functional activity	Standard Deviation 14.35
CSL830 (High Dose)	Modeled C1-esterase Inhibitor Functional Activity Trough Level	80.6 percent functional activity	Standard Deviation 23.47

Secondary

As-observed C1-esterase Inhibitor Functional Activity Trough Level

Mean trough C1-esterase inhibitor functional activity of the low, medium and high subcutaneous dose regimens

Time frame: during the last week of 4-week dose regimen

Population: As-observed analysis set - subset of the full analysis set (FAS). FAS consisted of all enrolled subjects (all subjects who gave informed consent).

Arm	Measure	Value (MEAN)	Dispersion
CSL830 (Low Dose)	As-observed C1-esterase Inhibitor Functional Activity Trough Level	31.7 percent functional activity	Standard Deviation 9.97
CSL830 (Medium Dose)	As-observed C1-esterase Inhibitor Functional Activity Trough Level	44.3 percent functional activity	Standard Deviation 17.73
CSL830 (High Dose)	As-observed C1-esterase Inhibitor Functional Activity Trough Level	80.5 percent functional activity	Standard Deviation 24.92

Secondary

C1-esterase Inhibitor Concentration Trough Level

Mean trough C1-esterase inhibitor concentration of the low, medium and high subcutaneous dose regimens

Time frame: during the last week of 4-week dose regimen