Hereditary Angioedema
Conditions
Keywords
Hereditary angioedema, C1 esterase inhibitor (human)
Brief summary
The study objective was to evaluate the safety and efficacy of repeat use of C1INH-nf for the treatment of acute HAE attacks.
Detailed description
A total of 113 subjects were enrolled in the study. One-hundred-one (101) subjects received C1INH-nf for the treatment of 1 or more HAE attacks and were analyzed for efficacy. The study design also allowed for short-term prophylaxis with C1INH-nf prior to emergency or non-cosmetic surgical or dental procedures, and an additional 12 subjects received C1INH-nf only for this purpose. All 113 subjects were exposed to C1INH-nf and analyzed for safety.
Interventions
BIOLOGICALC1 esterase inhibitor [human] (C1INH-nf)
Sponsors
Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to No maximum
Healthy volunteers
No
Inclusion criteria
This study was open to all subjects who: * Completed participation in LEVP2005-1/A (NCT00289211) and were not participating in LEVP2005-1/B (NCT01005888), any time after the 3-day telephone follow-up * Completed participation in LEVP2005-1/B any time after the final prophylactic therapy in Part B * Were enrolled but not randomized in LEVP2005-1/A after Part A was closed * Were excluded from LEVP2005-1 for any of the following reasons: * Pregnancy or lactation * Age less than 6 years * Narcotic addiction * Presence of anti-C1INH autoantibodies * Were not enrolled in LEVP2005-1 after enrollment in LEVP2005-1 was closed, under the following circumstances: * Had a diagnosis of HAE: evidence of a low C4 level plus either a low C1INH antigenic level or a low C1INH functional level, or * Had a known HAE-causing C1INH mutation, or * Had a diagnosis of HAE based on a strong family history of HAE as determined by the principal investigator
Exclusion criteria
* History of allergic reaction to C1INH or other blood products * Participated in any other investigational drug study within the past 30 days * Received blood or a blood product in the past 60 days other than C1INH-nf
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Hereditary Angioedema (HAE) Attacks Treated With C1INH-nf | Duration of the study (2.5 years) | — |
| Percent of HAE Attacks With Substantial Relief of the Defining Symptom | Within 4 hours after initial treatment | Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose or until substantial relief of the defining symptom was achieved. The conservative analysis defined substantial relief as 3 consecutive assessments of improvement of the defining symptom; any attack that did not have 3 consecutive documented reports of improvement was considered a treatment failure. In the less conservative analysis, attacks also were considered to have responded if clinical improvement of the defining symptom occurred but data were incomplete due to cessation of symptom assessments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antigenic C1 Inhibitor (C1INH) Serum Levels | Pre-infusion to 1 hour post-infusion | Change in antigenic C1INH serum levels from pre-infusion to 1 hour after the initial dose of study drug. |
| Time to Beginning of Substantial Relief of the Defining Symptom | Within 4 hours after initial treatment | Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose 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. |
| Complement C4 Serum Levels | Pre-infusion to 1 hour post-infusion | Change in complement C4 serum levels from pre-infusion to 1 hour after the initial dose of study drug. |
| Functional C1INH Serum Levels | Pre-infusion to 1 hour post-infusion | Percent change in functional C1INH serum levels from pre-infusion to 1 hour after the initial dose of study drug. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (ie, functional C1INH/total detectable C1INH). |
| Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Within 4 hours after initial treatment | For attack number 1, the number of censored observations precluded estimation of the 95% confidence interval (CI) upper bound for median time to event (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). Entry of 4.0 hours indicates that data were not estimable (NE); as non-numeric data are not supported by the 95% CI field, entry of the actual result (ie, NE or \>4.0) was not possible. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Open-label 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. | 113 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | 3-month follow-up no longer required | 12 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 6 |
| Overall Study | Noncompliance with protocol requirements | 9 |
| Overall Study | Transferred to LEVP2006-4 (NCT00462709) | 30 |
| Overall Study | Transitioned to commercial C1INH-nf | 6 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Open-label C1INH-nf |
|---|---|
| Age, Continuous | 34.5 years STANDARD_DEVIATION 17.6 |
| Sex: Female, Male Female | 75 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 113 |
| serious Total, serious adverse events | 0 / 113 |
Outcome results
Primary
Number of Hereditary Angioedema (HAE) Attacks Treated With C1INH-nf
Time frame: Duration of the study (2.5 years)
Population: Intent-to-treat Efficacy (ITT-E) Population (N=101; the number of subjects who received at least one dose of C1INH-nf for the treatment of an acute HAE attack).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open-label C1INH-nf | Number of Hereditary Angioedema (HAE) Attacks Treated With C1INH-nf | Conservative Analysis | 609 attacks |
| Open-label C1INH-nf | Number of Hereditary Angioedema (HAE) Attacks Treated With C1INH-nf | Less Conservative Analysis | 598 attacks |
Primary
Percent of HAE Attacks With Substantial Relief of the Defining Symptom
Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose or until substantial relief of the defining symptom was achieved. The conservative analysis defined substantial relief as 3 consecutive assessments of improvement of the defining symptom; any attack that did not have 3 consecutive documented reports of improvement was considered a treatment failure. In the less conservative analysis, attacks also were considered to have responded if clinical improvement of the defining symptom occurred but data were incomplete due to cessation of symptom assessments.
Time frame: Within 4 hours after initial treatment
Population: ITT-E Population (N=101; the number of subjects who received at least one dose of C1INH-nf for the treatment of an acute HAE attack).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open-label C1INH-nf | Percent of HAE Attacks With Substantial Relief of the Defining Symptom | Conservative Analysis | 87 percent of attacks |
| Open-label C1INH-nf | Percent of HAE Attacks With Substantial Relief of the Defining Symptom | Less Conservative Analysis | 95 percent of attacks |
Secondary
Antigenic C1 Inhibitor (C1INH) Serum Levels
Change in antigenic C1INH serum levels from pre-infusion to 1 hour after the initial dose of study drug.
Time frame: Pre-infusion to 1 hour post-infusion
Population: ITT-E subjects with data at both sampling time points (N=84).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-label C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Pre-infusion | 10.7 mg/dL | Standard Deviation 13.91 |
| Open-label C1INH-nf | Antigenic C1 Inhibitor (C1INH) Serum Levels | Increase at 1 hour post-infusion | 9.6 mg/dL | Standard Deviation 12.98 |
Secondary
Complement C4 Serum Levels
Change in complement C4 serum levels from pre-infusion to 1 hour after the initial dose of study drug.
Time frame: Pre-infusion to 1 hour post-infusion
Population: ITT-E subjects with data at both sampling time points (N=74).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-label C1INH-nf | Complement C4 Serum Levels | Pre-infusion | 5.3 mg/dL | Standard Deviation 5.41 |
| Open-label C1INH-nf | Complement C4 Serum Levels | Change at 1 hour post-infusion | -0.2 mg/dL | Standard Deviation 1.51 |
Secondary
Functional C1INH Serum Levels
Percent change in functional C1INH serum levels from pre-infusion to 1 hour after the initial dose of 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 hour post-infusion
Population: ITT-E subjects with data at both sampling time points (N=82).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Open-label C1INH-nf | Functional C1INH Serum Levels | Pre-infusion | 27.0 percent of functional C1INH | Standard Deviation 19.3 |
| Open-label C1INH-nf | Functional C1INH Serum Levels | Percent increase at 1 hour post-infusion | 39.2 percent of functional C1INH | Standard Deviation 18.04 |
Secondary
Time to Beginning of Substantial Relief of the Defining Symptom
Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose 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-E Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom | 0.75 hours |
Secondary
Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments
For attack number 1, the number of censored observations precluded estimation of the 95% confidence interval (CI) upper bound for median time to event (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). Entry of 4.0 hours indicates that data were not estimable (NE); as non-numeric data are not supported by the 95% CI field, entry of the actual result (ie, NE or \>4.0) was not possible.
Time frame: Within 4 hours after initial treatment
Population: ITT-E subjects with at least 10 HAE attacks during the study (N=15).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 1 | 1.50 hours |
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 2 | 0.50 hours |
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 3 | 0.50 hours |
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 4 | 0.50 hours |
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 5 | 0.75 hours |
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 6 | 0.50 hours |
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 7 | 0.75 hours |
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 8 | 0.50 hours |
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 9 | 0.25 hours |
| Open-label C1INH-nf | Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments | Attack number 10 | 0.50 hours |