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 prevention of acute HAE attacks.
Detailed description
Subjects were given diary cards and instructed to document all HAE attacks on a daily basis. Subjects evaluated their symptoms over the previous 24 hours, noting the severity and duration of swelling at each of 5 locations (abdominal, genitourinary, facial, respiratory \[including laryngeal\], and/or extremity). The study design also allowed for administration of open-label C1INH-nf (1,000 U of C1INH-nf administered IV \[repeated after 60 minutes, if necessary\] for treatment of laryngeal angioedema or if deemed necessary by the investigator; 1,000 U of C1INH-nf administered IV \[single dose\] prior to emergency surgical procedures). A total of 26 subjects were enrolled in the study. One subject received open-label C1INH-nf but withdrew prior to randomization. Another subject was randomized but withdrew prior to receiving study drug. Twenty-four (24) subjects were randomized and treated with blinded study drug. In total, 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 subjects were exposed to C1INH-nf and 23 subjects were exposed to placebo.
Interventions
BIOLOGICALC1 esterase inhibitor [human] (C1INH-nf)
DRUGPlacebo (saline)
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented HAE * Normal C1q level * Relatively frequent angioedema attacks (at least 2 per month on average)
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 |
|---|---|---|
| Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period | 12 weeks | An HAE attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day. Analyses include observed attack counts and normalized attack counts (i.e., the number of attacks observed during each therapy period, normalized for the number of days the subject participated in that period). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subject Withdrawals During Each Prophylactic Therapy Period | 12 weeks | At the end of each therapy period, each subject was assigned a yes/no drop-out status. A drop-out was defined as a subject who did not have a Week 12 visit record. |
| Average Severity of HAE Attacks During Each Prophylactic Therapy Period | 12 weeks | All attacks in each therapy period were assigned a value of 1 (mild), 2 (moderate), or 3 (severe). Attack severity was considered the highest value assigned by the subject to any swelling location during the attack. Average severity was set to 0 if there was no attack in a period. |
| Average Duration of HAE Attacks During Each Prophylactic Therapy Period | 12 weeks | The duration of an attack was measured from the first report of swelling at any one of the five locations (abdominal, genitourinary, facial, respiratory \[including laryngeal\], or extremity) until the first subsequent report of no swelling at all five locations. |
| Antigenic C1 Inhibitor (C1INH) Serum Levels | Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12 | Change in antigenic C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits. |
| Functional C1INH Serum Levels | Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12 | Percent change in functional C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (i.e., functional C1INH/total detectable C1INH). |
| Number of Open-label C1INH-nf Infusions Required During Each Prophylactic Therapy Period | 12 weeks | The study design allowed for subjects to be treated with open-label C1INH-nf for laryngeal angioedema, if deemed necessary by the investigator, or prior to emergency surgical procedures. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Days of Swelling During Each Prophylactic Therapy Period | 12 weeks | A day of swelling was defined as a day that a subject reported swelling at any of the five locations (abdominal, genitourinary, facial, respiratory \[including laryngeal\], or extremity). |
Countries
United States
Participant flow
Pre-assignment details
A total of 26 subjects were enrolled in the study (see Detailed Description). One subject received open-label C1 esterase inhibitor (C1INH-nf) but withdrew prior to randomization. Another subject was randomized but withdrew prior to receiving study drug. 24 subjects were randomized and began therapy with blinded study drug in Period 1.
Participants by arm
| Arm | Count |
|---|---|
| C1INH-nf First, Then Placebo 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by matching placebo (saline) administered IV every 3 to 4 days for 12 weeks. | 12 |
| Placebo First, Then C1INH-nf Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by 1,000 U of C1INH-nf administered IV every 3 to 4 days for 12 weeks. | 12 |
| Open-label C1INH-nf Only One subject received open-label C1INH-nf but withdrew prior to randomization. | 1 |
| Randomized, Not Treated One subject was randomized but withdrew prior to receiving study drug. | 1 |
| Total | 26 |
Baseline characteristics
| Characteristic | C1INH-nf First, Then Placebo | Placebo First, Then C1INH-nf | Open-label C1INH-nf Only | Randomized, Not Treated | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 5 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 10 Participants | 1 Participants | 0 Participants | 20 Participants |
| Sex: Female, Male Female | 9 Participants | 12 Participants | 1 Participants | 0 Participants | 22 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 25 | 0 / 23 |
| serious Total, serious adverse events | 0 / 25 | 0 / 23 |
Outcome results
Primary
Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period
An HAE attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day. Analyses include observed attack counts and normalized attack counts (i.e., the number of attacks observed during each therapy period, normalized for the number of days the subject participated in that period).
Time frame: 12 weeks
Population: The Efficacy Dataset (N=22) consisted of all randomized subjects who completed 12 weeks of therapy in Period 1 and received at least one infusion of study drug in Period 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C1INH-nf | Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period | Observed | 6.1 attacks | Standard Deviation 5.43 |
| C1INH-nf | Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period | Normalized | 6.3 attacks | Standard Deviation 5.54 |
| Placebo | Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period | Observed | 12.7 attacks | Standard Deviation 4.8 |
| Placebo | Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period | Normalized | 12.7 attacks | Standard Deviation 4.65 |
p-value: <0.0001ANOVA
p-value: <0.0001ANOVA
Secondary
Antigenic C1 Inhibitor (C1INH) Serum Levels
Change in antigenic C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits.
Time frame: Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12
Population: Efficacy Dataset subjects with data at both sampling time points (N=19 C1INH-nf, N=22 placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Visit 1 change at 1 hour post-infusion | 7.9 mg/dL | Standard Deviation 3.7 |
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Week 8 change at 1 hour post-infusion | 7.2 mg/dL | Standard Deviation 5.62 |
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Week 4 change at 1 hour post-infusion | 9.8 mg/dL | Standard Deviation 5.08 |
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Week 12 change at 1 hour post-infusion | 8.4 mg/dL | Standard Deviation 5.93 |
| C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Visit 1 pre-infusion | 14.3 mg/dL | Standard Deviation 15.08 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Week 12 change at 1 hour post-infusion | 1.1 mg/dL | Standard Deviation 5.98 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Visit 1 pre-infusion | 14.2 mg/dL | Standard Deviation 14.71 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Visit 1 change at 1 hour post-infusion | -0.1 mg/dL | Standard Deviation 2.17 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Week 4 change at 1 hour post-infusion | 0.1 mg/dL | Standard Deviation 5.04 |
| Placebo | Antigenic C1 Inhibitor (C1INH) Serum Levels | Week 8 change at 1 hour post-infusion | -0.3 mg/dL | Standard Deviation 3.08 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: 0.0001Wilcoxon (Mann-Whitney)
p-value: 0.0028Wilcoxon (Mann-Whitney)
Secondary
Average Duration of HAE Attacks During Each Prophylactic Therapy Period
The duration of an attack was measured from the first report of swelling at any one of the five locations (abdominal, genitourinary, facial, respiratory \[including laryngeal\], or extremity) until the first subsequent report of no swelling at all five locations.
Time frame: 12 weeks
Population: Efficacy Dataset.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C1INH-nf | Average Duration of HAE Attacks During Each Prophylactic Therapy Period | 2.1 days | Standard Deviation 1.13 |
| Placebo | Average Duration of HAE Attacks During Each Prophylactic Therapy Period | 3.4 days | Standard Deviation 1.39 |
p-value: 0.0004Wilcoxon (Mann-Whitney)
Secondary
Average Severity of HAE Attacks During Each Prophylactic Therapy Period
All attacks in each therapy period were assigned a value of 1 (mild), 2 (moderate), or 3 (severe). Attack severity was considered the highest value assigned by the subject to any swelling location during the attack. Average severity was set to 0 if there was no attack in a period.
Time frame: 12 weeks
Population: Efficacy Dataset.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C1INH-nf | Average Severity of HAE Attacks During Each Prophylactic Therapy Period | 1.3 units on a scale | Standard Deviation 0.85 |
| Placebo | Average Severity of HAE Attacks During Each Prophylactic Therapy Period | 1.9 units on a scale | Standard Deviation 0.35 |
p-value: 0.0008Wilcoxon (Mann-Whitney)
Secondary
Functional C1INH Serum Levels
Percent change in functional C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (i.e., functional C1INH/total detectable C1INH).
Time frame: Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12
Population: Efficacy Dataset subjects with data at both sampling time points (N=20 C1INH-nf, N=22 placebo).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C1INH-nf | Functional C1INH Serum Levels | Visit 1 percent change at 1 hour post-infusion | 32.0 percent of functional C1INH | Standard Deviation 18.95 |
| C1INH-nf | Functional C1INH Serum Levels | Week 8 percent change at 1 hour post-infusion | 32.1 percent of functional C1INH | Standard Deviation 19.08 |
| C1INH-nf | Functional C1INH Serum Levels | Week 4 percent change at 1 hour post-infusion | 36.6 percent of functional C1INH | Standard Deviation 17.62 |
| C1INH-nf | Functional C1INH Serum Levels | Week 12 percent change at 1 hour post-infusion | 33.9 percent of functional C1INH | Standard Deviation 21.07 |
| C1INH-nf | Functional C1INH Serum Levels | Visit 1 pre-infusion | 33.9 percent of functional C1INH | Standard Deviation 17.21 |
| Placebo | Functional C1INH Serum Levels | Week 12 percent change at 1 hour post-infusion | 0.8 percent of functional C1INH | Standard Deviation 23.92 |
| Placebo | Functional C1INH Serum Levels | Visit 1 pre-infusion | 31.7 percent of functional C1INH | Standard Deviation 21.54 |
| Placebo | Functional C1INH Serum Levels | Visit 1 percent change at 1 hour post-infusion | -2.4 percent of functional C1INH | Standard Deviation 9.41 |
| Placebo | Functional C1INH Serum Levels | Week 4 percent change at 1 hour post-infusion | 5.3 percent of functional C1INH | Standard Deviation 26.16 |
| Placebo | Functional C1INH Serum Levels | Week 8 percent change at 1 hour post-infusion | 5.4 percent of functional C1INH | Standard Deviation 15.74 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: 0.0002Wilcoxon (Mann-Whitney)
Secondary
Number of Open-label C1INH-nf Infusions Required During Each Prophylactic Therapy Period
The study design allowed for subjects to be treated with open-label C1INH-nf for laryngeal angioedema, if deemed necessary by the investigator, or prior to emergency surgical procedures.
Time frame: 12 weeks
Population: Efficacy Dataset.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C1INH-nf | Number of Open-label C1INH-nf Infusions Required During Each Prophylactic Therapy Period | 4.7 infusions | Standard Deviation 8.66 |
| Placebo | Number of Open-label C1INH-nf Infusions Required During Each Prophylactic Therapy Period | 15.4 infusions | Standard Deviation 8.41 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Number of Subject Withdrawals During Each Prophylactic Therapy Period
At the end of each therapy period, each subject was assigned a yes/no drop-out status. A drop-out was defined as a subject who did not have a Week 12 visit record.
Time frame: 12 weeks
Population: The Safety Dataset (N=24) consisted of all randomized subjects who received at least 1 complete or partial infusion of study drug. 24 subjects began Period 1 (12 C1INH-nf, 12 placebo) and received study drug. 22 subjects crossed over to Period 2 (11 placebo, 11 C1INH-nf) and received study drug. Thus, 23 randomized subjects received each therapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| C1INH-nf | Number of Subject Withdrawals During Each Prophylactic Therapy Period | Period 1 | 1 participants |
| C1INH-nf | Number of Subject Withdrawals During Each Prophylactic Therapy Period | Period 2 | 1 participants |
| Placebo | Number of Subject Withdrawals During Each Prophylactic Therapy Period | Period 1 | 1 participants |
| Placebo | Number of Subject Withdrawals During Each Prophylactic Therapy Period | Period 2 | 1 participants |
p-value: >0.999Fisher Exact
p-value: >0.999Fisher Exact
Other Pre-specified
Total Number of Days of Swelling During Each Prophylactic Therapy Period
A day of swelling was defined as a day that a subject reported swelling at any of the five locations (abdominal, genitourinary, facial, respiratory \[including laryngeal\], or extremity).
Time frame: 12 weeks
Population: Efficacy Dataset.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C1INH-nf | Total Number of Days of Swelling During Each Prophylactic Therapy Period | 10.1 days | Standard Deviation 10.73 |
| Placebo | Total Number of Days of Swelling During Each Prophylactic Therapy Period | 29.6 days | Standard Deviation 16.9 |
p-value: <0.0001Wilcoxon (Mann-Whitney)