Hereditary Angioedema
Conditions
Keywords
Hereditary angioedema, HAE, C1 esterase inhibitor (human), C1INH-nf
Brief summary
The study objective was to determine the safety and efficacy of C1INH-nf for the treatment of acute HAE attacks.
Detailed description
Randomized subjects treated for a qualifying attack were eligible to receive rescue dosing with 1,000 U of C1INH-nf if they did not achieve beginning of substantial relief of the defining symptom within 4 hours after initial treatment with blinded study drug, or if at any time the attack progressed to include airway compromise. A second 1,000 U rescue dose was permitted 60 minutes after the initial rescue dose, if necessary. The study design also allowed for administration of open-label C1INH-nf for laryngeal angioedema attacks, which were non-randomizable events due to the presence of or potential for airway compromise (immediate 1,000 U dose of C1INH-nf, repeated after 60 minutes, if necessary). In addition, subjects were eligible to receive open-label C1INH-nf (1,000 U single dose) prior to emergency surgical (non-cosmetic) procedures. A total of 83 subjects were enrolled in the study. Seventy-one (71) subjects experienced qualifying attacks and were randomized to blinded study drug (36 C1INH-nf, 35 placebo); only the 71 randomized subjects were analyzed for efficacy. An additional 12 subjects were never randomized but received open-label C1INH-nf for treatment of laryngeal angioedema and/or prior to emergency surgical procedures. Of the 35 subjects randomized to placebo, 23 also received C1INH-nf (eg, rescue, open-label). In total, 83 subjects received at least 1 dose of study drug and were analyzed for safety; 71 subjects were exposed to C1INH-nf (59 randomized, 12 open-label only) and 12 subjects were exposed only to placebo.
Interventions
BIOLOGICALC1 esterase inhibitor [human] (C1INH-nf)
DRUGPlacebo (saline)
Sponsors
Shire
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
* Documented HAE * Normal C1q level
Exclusion criteria
* Low C1q level * B-cell malignancy * Presence of anti-C1INH autoantibody * History of allergic reaction to C1INH or other blood products * Narcotic addiction * Current participation in any other investigational drug study or within the past 30 days * Participation in a C1 esterase inhibitor trial, or received blood or a blood product in the past 90 days * Pregnancy or lactation * Any clinically significant medical condition, such as renal failure, that in the opinion of the investigator would interfere with the subject's ability to participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Beginning of Substantial Relief of the Defining Symptom | Within 4 hours after initial treatment | Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug or until substantial relief of the defining symptom was achieved. Substantial relief was defined as 3 consecutive assessments of improvement of the defining symptom. Beginning of substantial relief was considered the first of the 3 consecutive assessments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Beginning of Substantial Relief of the Defining Symptom | Within 4 hours after initial treatment | Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug or until substantial relief of the defining symptom was achieved. Substantial relief was defined as 3 consecutive assessments of improvement of the defining symptom. Beginning of substantial relief was considered the first of the 3 consecutive assessments. |
| Time to Complete Resolution of the HAE Attack | 72 hours | Randomized subjects were contacted 72-96 hours (3-4 days) after discharge from the study site to determine when complete resolution of the HAE attack occurred. |
| Antigenic C1 Inhibitor (C1INH) Serum Levels | Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion | Change in antigenic C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug. |
| Functional C1INH Serum Levels | Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion | Percent change in functional C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (ie, functional C1INH/total detectable C1INH). |
| Complement C4 Serum Levels | Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion | Change in complement C4 serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| C1INH-nf 1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered. | 36 |
| Placebo Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered. | 35 |
| Open-label C1INH-nf Only Twelve subjects were never randomized but received open-label C1INH-nf for treatment of laryngeal angioedema and/or prior to emergency surgical procedures. These subjects were analyzed for safety only. | 12 |
| Total | 83 |
Baseline characteristics
| Characteristic | C1INH-nf | Placebo | Open-label C1INH-nf Only | Total |
|---|---|---|---|---|
| Age, Continuous | 36.8 years STANDARD_DEVIATION 17.68 | 37.0 years STANDARD_DEVIATION 13.76 | 36.3 years STANDARD_DEVIATION 19.42 | 36.8 years STANDARD_DEVIATION 16.2 |
| Sex: Female, Male Female | 27 Participants | 28 Participants | 6 Participants | 61 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 6 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 71 | 1 / 12 |
| serious Total, serious adverse events | 0 / 71 | 0 / 12 |
Outcome results
Primary
Time to Beginning of Substantial Relief of the Defining Symptom
Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug or until substantial relief of the defining symptom was achieved. Substantial relief was defined as 3 consecutive assessments of improvement of the defining symptom. Beginning of substantial relief was considered the first of the 3 consecutive assessments.
Time frame: Within 4 hours after initial treatment
Population: Intent-to-treat (ITT) Population (all randomized subjects). Since less than 50% of subjects in the placebo group achieved the endpoint, median time to event was not estimable (NE). Further, the number of censored events in the C1INH-nf and placebo groups precluded estimation of the 95% confidence interval (CI) upper bound for median time to event.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom | 2.0 hours |
| Placebo | Time to Beginning of Substantial Relief of the Defining Symptom | 4.0 hours |
Comparison: Subjects who did not experience beginning of substantial relief of the defining symptom within 4 hours after initial treatment were included in the analysis as censored observations. Entries of 4.0 (hours) for median time to event or 95% CI indicate that data were NE (see Population Description). As non-numeric data are not supported by the median and 95% CI fields, entry of the actual results (ie, NE or \>4.0) was not possible.p-value: 0.04895% CI: [1.008, 4.164]Regression, Cox
Secondary
Antigenic C1 Inhibitor (C1INH) Serum Levels
Change in antigenic C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug.
Time frame: Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion
Population: ITT-E subjects (N=68) with data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Change at 1 hour post-infusion (N=35, N=32) | 6.7 mg/dL | Standard Deviation 8.86 |
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Change at 4 hours post-infusion (N=28, N=23) | 8.6 mg/dL | Standard Deviation 8.92 |
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Change at 2 hours post-infusion (N=23, N=27) | 11.7 mg/dL | Standard Deviation 12.86 |
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Change at 12 hours post-infusion (N=19, N=13) | 5.6 mg/dL | Standard Deviation 11.21 |
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Pre-infusion (N=34, N=33) | 14.7 mg/dL | Standard Deviation 22.21 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Change at 12 hours post-infusion (N=19, N=13) | -0.8 mg/dL | Standard Deviation 4.39 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Pre-infusion (N=34, N=33) | 13.0 mg/dL | Standard Deviation 16.42 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Change at 1 hour post-infusion (N=35, N=32) | -0.9 mg/dL | Standard Deviation 9.25 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Change at 2 hours post-infusion (N=23, N=27) | 0.5 mg/dL | Standard Deviation 6.73 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Change at 4 hours post-infusion (N=28, N=23) | 0.4 mg/dL | Standard Deviation 6.72 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: 0.0007Wilcoxon (Mann-Whitney)
Secondary
Complement C4 Serum Levels
Change in complement C4 serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug.
Time frame: Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion
Population: ITT-E subjects (N=68) with data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C1INH-nf | Complement C4 Serum Levels | Change at 1 hour post-infusion (N=33, N=30) | -0.7 mg/dL | Standard Deviation 5.59 |
| C1INH-nf | Complement C4 Serum Levels | Change at 4 hours post-infusion (N=26, N=22) | -1.0 mg/dL | Standard Deviation 5.62 |
| C1INH-nf | Complement C4 Serum Levels | Pre-infusion (N=35, N=32) | 8.1 mg/dL | Standard Deviation 7.79 |
| C1INH-nf | Complement C4 Serum Levels | Change at 12 hours post-infusion (N=19, N=14) | 2.9 mg/dL | Standard Deviation 6.33 |
| C1INH-nf | Complement C4 Serum Levels | Change at 2 hours post-infusion (N=21, N=26) | -1.7 mg/dL | Standard Deviation 8.12 |
| Placebo | Complement C4 Serum Levels | Change at 12 hours post-infusion (N=19, N=14) | 0.1 mg/dL | Standard Deviation 2.07 |
| Placebo | Complement C4 Serum Levels | Change at 1 hour post-infusion (N=33, N=30) | -0.9 mg/dL | Standard Deviation 1.96 |
| Placebo | Complement C4 Serum Levels | Change at 2 hours post-infusion (N=21, N=26) | -1.1 mg/dL | Standard Deviation 2.13 |
| Placebo | Complement C4 Serum Levels | Change at 4 hours post-infusion (N=26, N=22) | -0.5 mg/dL | Standard Deviation 1.9 |
| Placebo | Complement C4 Serum Levels | Pre-infusion (N=35, N=32) | 6.7 mg/dL | Standard Deviation 5.32 |
p-value: 0.1321Wilcoxon (Mann-Whitney)
p-value: 0.5218Wilcoxon (Mann-Whitney)
p-value: 0.121Wilcoxon (Mann-Whitney)
p-value: 0.0017Wilcoxon (Mann-Whitney)
Secondary
Functional C1INH Serum Levels
Percent change in functional C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (ie, functional C1INH/total detectable C1INH).
Time frame: Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion
Population: ITT-E subjects (N=68) with data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C1INH-nf | Functional C1INH Serum Levels | Percent change 1 hour post-infusion (N=35, N=32) | 31.5 percent of functional C1INH | Standard Deviation 23.94 |
| C1INH-nf | Functional C1INH Serum Levels | Percent change 4 hours post-infusion (N=28, N=25) | 34.5 percent of functional C1INH | Standard Deviation 28.22 |
| C1INH-nf | Functional C1INH Serum Levels | Percent change 2 hours post-infusion (N=23, N=26) | 45.6 percent of functional C1INH | Standard Deviation 23.7 |
| C1INH-nf | Functional C1INH Serum Levels | Percent change 12 hours post-infusion (N=19, N=14) | 34.8 percent of functional C1INH | Standard Deviation 17.24 |
| C1INH-nf | Functional C1INH Serum Levels | Pre-infusion (N=34, N=31) | 35.6 percent of functional C1INH | Standard Deviation 22.62 |
| Placebo | Functional C1INH Serum Levels | Percent change 12 hours post-infusion (N=19, N=14) | 5.1 percent of functional C1INH | Standard Deviation 32.09 |
| Placebo | Functional C1INH Serum Levels | Pre-infusion (N=34, N=31) | 33.7 percent of functional C1INH | Standard Deviation 29.04 |
| Placebo | Functional C1INH Serum Levels | Percent change 1 hour post-infusion (N=35, N=32) | -6.4 percent of functional C1INH | Standard Deviation 23.73 |
| Placebo | Functional C1INH Serum Levels | Percent change 2 hours post-infusion (N=23, N=26) | 1.0 percent of functional C1INH | Standard Deviation 12.43 |
| Placebo | Functional C1INH Serum Levels | Percent change 4 hours post-infusion (N=28, N=25) | 4.3 percent of functional C1INH | Standard Deviation 26.02 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: 0.0022Wilcoxon (Mann-Whitney)
Secondary
Number of Subjects With Beginning of Substantial Relief of the Defining Symptom
Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug or until substantial relief of the defining symptom was achieved. Substantial relief was defined as 3 consecutive assessments of improvement of the defining symptom. Beginning of substantial relief was considered the first of the 3 consecutive assessments.
Time frame: Within 4 hours after initial treatment
Population: ITT-Efficacy (ITT-E) Population (N=68; 3 of the 71 randomized \[ie, ITT\] subjects were excluded from the ITT-E Population, as it was later determined that they did not experience a definitive hereditary angioedema \[HAE\] attack).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1INH-nf | Number of Subjects With Beginning of Substantial Relief of the Defining Symptom | 21 participants |
| Placebo | Number of Subjects With Beginning of Substantial Relief of the Defining Symptom | 14 participants |
p-value: 0.06295% CI: [0.87, 2.29]Cochran-Mantel-Haenszel
Secondary
Time to Complete Resolution of the HAE Attack
Randomized subjects were contacted 72-96 hours (3-4 days) after discharge from the study site to determine when complete resolution of the HAE attack occurred.
Time frame: 72 hours
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| C1INH-nf | Time to Complete Resolution of the HAE Attack | 12.3 hours |
| Placebo | Time to Complete Resolution of the HAE Attack | 31.6 hours |
Comparison: Subjects who had not experienced complete resolution of the HAE attack at the time of the follow-up telephone call, or who were lost to follow-up, were censored at 72 hours.p-value: 0.00195% CI: [1.471, 5.02]Regression, Cox