Recombinant Human C1 Inhibitor for the Treatment of Acute Attacks in Patients With Hereditary Angioedema
Study Details
Study Description
Brief Summary
Hereditary angioedema ("HAE") is a genetic disorder characterized by sudden recurrent attacks of local swelling (angioedema). These attacks are often painful and disabling, and, in some cases, life-threatening. "HAE" is caused by mutations in the "C1INH" gene that leads to a decrease in the blood level of functional "C1INH". This multi-center study was designed to assess the safety and tolerability, efficacy and pharmacodynamics/ pharmacokinetics of recombinant human C1 inhibitor ("rhC1INH") in the treatment of acute hereditary angioedema attacks.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
A prospectively planned interim analysis will be performed on the double-blind data.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 100 IU/kg "rhC1INH" 100 IU/kg recombinant human C1 inhibitor |
Drug: recombinant human C1 inhibitor
IV
Other Names:
|
| Placebo Comparator: Saline Saline solution |
Drug: Placebo
IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Time to Beginning of Relief of Symptoms [up to 48 hours after study drug administration]
The time to beginning of relief of symptoms has been assessed by using a patient-reported visual analogue scale ("VAS") ranging from 0 mm (no symptoms at all) to 100 mm (extremely disabling). Time to beginning of relief of symptoms at the location that showed first "VAS" score decrease of at least 20 mm from baseline score (t= 0 min) to the next assessment time-point). Assessment time-points were taken on pre-scheduled time-points after drug administration: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to beginning of relief has been calculated as median time, by using the exact time-points on which each assessment was performed.
Secondary Outcome Measures
- Time to Minimal Symptoms [up to 48 hours after study drug administration]
the time to minimal symptoms was the time to minimal symptoms for an attack, assessed using the Visual Analogue Scale ("VAS") score. Symptoms were said to be minimal when the "VAS" score at all locations was below 20 mm. Assessment time-points were: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to minimal symptoms has been calculated by using the exact time-points on which each assessment was performed.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Clear clinical and laboratory diagnosis of HAE
-
Baseline plasma level of functional C1INH of less than 50% of normal
-
Evidence for exacerbation or development of a severe abdominal, oro-facial/ pharyngeal/ laryngeal, genito-urinary and/or peripheral HAE attack
Exclusion Criteria:
-
Acquired angioedema
-
Pregnancy or breastfeeding
-
Participation in another clinical study within prior 3 months
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | For information on sites, please contact Pharming Medical Affairs Deparment | Leiden | Netherlands | 2300 AL | |
| 2 | Emergency County Hospital, Internal Medicin Clinica, Allergology-Immunology Department | Tirgu Mures | Romania | 541103 |
Sponsors and Collaborators
- Pharming Technologies B.V.
Investigators
- Study Chair: Jan Nuijens, MD, PhD, Pharming Group N.V.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- C1 1304-01
Study Results
Participant Flow
| Recruitment Details | During the double-blind phase of the study, patients were randomized once to receive 100 IU/kg "rhC1INH" or Saline in a ratio of 1:1. After conclusion of the double-blind phase, patients with subsequent eligible attacks could be treated with open-label 1 vial (2100 IU) of "rhC1INH". |
|---|---|
| Pre-assignment Detail | Patients could be enrolled into the open-label phase of the study after conclusion of the double-blind phase. |
| Arm/Group Title | 100 IU/kg "rhC1INH" | Saline | 1 Vial (2100 IU) "rhC1INH" |
|---|---|---|---|
| Arm/Group Description | Includes all subjects randomized and who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. | Includes all subjects randomized and who received Saline solution in the double-blind phase. | Includes all subjects who received, 1 vial (2100 IU) open-label "rhC1INH" in the open-label extension phase. Patients received 1 vial initially and could receive an additional 1-2 vials within 4 hours at the investigator's discretion. |
| Period Title: Double-blind Phase | |||
| STARTED | 16 | 16 | 0 |
| COMPLETED | 15 | 15 | 0 |
| NOT COMPLETED | 1 | 1 | 0 |
| Period Title: Double-blind Phase | |||
| STARTED | 0 | 0 | 57 |
| COMPLETED | 0 | 0 | 57 |
| NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | 100 IU/kg "rhC1INH" | Saline | 1 Vial (2100 IU) "rhC1INH" | Total |
|---|---|---|---|---|
| Arm/Group Description | Includes all subjects randomized who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. | Includes all subjects randomized and who received Saline solution in the double-blind phase. | Includes all subjects who received 1 vial (2100 IU) open-label "rhC1INH" in the open-label extension phase. | Total of all reporting groups |
| Overall Participants | 16 | 16 | 43 | 75 |
| Age (Count of Participants) | ||||
| <=18 years |
1
6.3%
|
1
6.3%
|
9
20.9%
|
11
14.7%
|
| Between 18 and 65 years |
13
81.3%
|
12
75%
|
33
76.7%
|
58
77.3%
|
| >=65 years |
2
12.5%
|
3
18.8%
|
1
2.3%
|
6
8%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
8
50%
|
9
56.3%
|
28
65.1%
|
45
60%
|
| Male |
8
50%
|
7
43.8%
|
15
34.9%
|
30
40%
|
Outcome Measures
| Title | Time to Beginning of Relief of Symptoms |
|---|---|
| Description | The time to beginning of relief of symptoms has been assessed by using a patient-reported visual analogue scale ("VAS") ranging from 0 mm (no symptoms at all) to 100 mm (extremely disabling). Time to beginning of relief of symptoms at the location that showed first "VAS" score decrease of at least 20 mm from baseline score (t= 0 min) to the next assessment time-point). Assessment time-points were taken on pre-scheduled time-points after drug administration: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to beginning of relief has been calculated as median time, by using the exact time-points on which each assessment was performed. |
| Time Frame | up to 48 hours after study drug administration |
Outcome Measure Data
| Analysis Population Description |
|---|
| The full analysis set ("FAS" or "mITT") was defined as the set of patients who provided Informed Consent, were randomized and took at least one dose of the study drug administration. |
| Arm/Group Title | 100 IU/kg "rhC1INH" | Saline | 1 Vial (2100 IU) "rhC1INH" |
|---|---|---|---|
| Arm/Group Description | Includes all subjects randomized who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. | Includes all subjects randomized and who received Saline solution in the double-blind phase. | Includes all subjects who received 1 vial (2100 IU) open-label "rhC1INH" in the open-label extension phase. |
| Measure Participants | 16 | 16 | 57 |
| Median (Full Range) [minutes] |
62
|
508
|
61
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 100 IU/kg "rhC1INH", Saline |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.003 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Title | Time to Minimal Symptoms |
|---|---|
| Description | the time to minimal symptoms was the time to minimal symptoms for an attack, assessed using the Visual Analogue Scale ("VAS") score. Symptoms were said to be minimal when the "VAS" score at all locations was below 20 mm. Assessment time-points were: baseline (0 minutes), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 24 hours, 48 hours. Time to minimal symptoms has been calculated by using the exact time-points on which each assessment was performed. |
| Time Frame | up to 48 hours after study drug administration |
Outcome Measure Data
| Analysis Population Description |
|---|
| The full analysis set ("FAS" or "mITT") was defined as the set of patients who provided Informed Consent, were randomized and took at least one dose of study drug administration. |
| Arm/Group Title | 100 IU/kg "rhC1INH" | Saline | 1 Vial (2100 IU) "rhC1INH" |
|---|---|---|---|
| Arm/Group Description | Includes all subjects randomized who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. | Includes all subjects randomized and who received Saline solution in the double-blind phase. | Includes all subjects who received 1 vial (2100 IU) open-label "rhC1INH" in the open-label extension phase. |
| Measure Participants | 16 | 16 | 57 |
| Median (Full Range) [minutes] |
480
|
1440
|
241
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 100 IU/kg "rhC1INH", Saline |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.005 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
Adverse Events
| Time Frame | Treatment-Emergent-Adverse-Events ("TEAEs") were defined as events with start from onset of study drug administration. Serious Adverse events and Adverse events for each arm with onset dates within 7 days of study drug administration have been listed. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | 100 IU/kg "rhC1INH" | Saline | 1 Vial (2100 IU) "rhC1INH" | |||
| Arm/Group Description | Includes all subjects randomized who received 100 IU/kg recombinant human C1 inhibitor in the double-blind phase. | Includes all subjects randomized and who received Saline solution in the double-blind phase. | Includes all subjects who received 1 vial (2100 IU) open-label "rhC1INH" in the open-label extension phase. | |||
All Cause Mortality |
||||||
| 100 IU/kg "rhC1INH" | Saline | 1 Vial (2100 IU) "rhC1INH" | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| 100 IU/kg "rhC1INH" | Saline | 1 Vial (2100 IU) "rhC1INH" | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/16 (0%) | 2/16 (12.5%) | 0/57 (0%) | |||
| Hepatobiliary disorders | ||||||
| Biliary colic | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 | 0/57 (0%) | 0 |
| Investigations | ||||||
| Prostate examination | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 | 0/57 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| 100 IU/kg "rhC1INH" | Saline | 1 Vial (2100 IU) "rhC1INH" | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/16 (12.5%) | 5/16 (31.3%) | 6/57 (10.5%) | |||
| Gastrointestinal disorders | ||||||
| nausea | 0/16 (0%) | 0 | 0/16 (0%) | 0 | 3/57 (5.3%) | 3 |
| General disorders | ||||||
| pain | 0/16 (0%) | 0 | 2/16 (12.5%) | 2 | 0/57 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| pain in extremity | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 | 0/57 (0%) | 0 |
| Nervous system disorders | ||||||
| headache | 1/16 (6.3%) | 1 | 2/16 (12.5%) | 2 | 3/57 (5.3%) | 3 |
| Reproductive system and breast disorders | ||||||
| menstrual disorder | 1/16 (6.3%) | 1 | 0/16 (0%) | 0 | 0/57 (0%) | 0 |
| scrotal swelling | 1/16 (6.3%) | 1 | 0/16 (0%) | 0 | 0/57 (0%) | 0 |
| Vascular disorders | ||||||
| hypotension | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 | 0/57 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The investigator must provide a copy of any results communication to the sponsor for review at least 30 days prior to its submission or disclosure. The sponsor may request to delete information identified by sponsor as confidential information prior to submitting such manuscript and/or abstract for publication. For a multi-center study, the investigator must wait (i) at least 24 months after the study is completed at all sites or (ii) until after the multi-center publication.
Results Point of Contact
| Name/Title | Medical Affairs Department |
|---|---|
| Organization | Pharming Technologies BV |
| Phone | +31715247400 |
| medicalinfo@pharming.com |
- C1 1304-01